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Ontario Air Standards

For

Cadmium and Cadmium Compounds

June 2007

Standards Development Branch Ontario Ministry of the Environment

Ontario

Ontario Air Standards for Cadmium and Cadmium Compounds

Executive Summary

The Ontario Ministry of the Environment (MOE) has identified the need to develop and/or update air quality standards for priority contaminants. The Ministry’s Standards Plan, which was released in October, 1996 and revised in November, 1999, identified candidate substances for which current air quality standards will be reviewed or new standards developed. Cadmium and cadmium compounds were identified as a priority compound for review based on the pattern of use in Ontario and recent toxicological information that was published subsequent to the development of the existing guideline in 1974. Once a decision is made on the air standards, they will be incorporated into Ontario Regulation 419: Air Pollution – Local Air Quality (O. Reg. 419/05). The Ambient Air Quality Criterion (AAQC) will be incorporated into Schedule 3 of the regulation and the half hour standards will be incorporated into Schedule 2. An ‘Information Document’ containing a review of scientific and technical information relevant to setting an air quality standard for cadmium and cadmium compounds was previously posted on the Environmental Bill of Rights Registry for public comments. This was followed more recently by the posting of a document providing the rationale (‘Rationale Document’) for recommending an Ambient Air Quality Criterion (AAQC) and a half hour standard for cadmium and cadmium compounds. This document, referred to as the ‘Decision Document’, summarizes the comments received from stakeholders on the proposed standards and the Ministry responses to these comments. This document also provides the rationale for the decision on the air quality standards for cadmium and cadmium compounds.

Cadmium is classified as a heavy metal and found widely distributed in the air, soil, and fresh and salt water. It can also be detected in foliage, coal, and petroleum. The most common forms of cadmium are oxide, chloride, and sulfide/sulfate. The most common uses for cadmium include the production of nickel-cadmium rechargeable batteries, paint pigments, and anticorrosive metal coatings. Cadmium is also used in the manufacturing of electronic components and select metal alloys.

Cadmium releases to the air take place through both natural and anthropogenic processes. Rock erosion, forest fires, and volcanic eruptions release cadmium to the air. Anthropogenic sources of cadmium are largely from the industrial sector such as mining, metal refining, and the combustion of fossil fuels.

The approximate airborne cadmium levels found in environments free of anthropogenic activity are of the order of 0.1 to 5 nanograms per cubic meter depending on other sources as will be discussed later. In urban environments in Ontario, cadmium levels as high as 3.44 nanograms per cubic meter have been measured.

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The primary form of cadmium to which the general population in Ontario is expected to be exposed to is cadmium oxide. Therefore, although discussions on toxicity assessment of various species of cadmium are presented, the emphasis in the development of the standard will be cadmium oxide.

This document reviews the adverse health effects due to cadmium-in-air exposure with an emphasis on the inhalation pathway. Cadmium in particulate matter in the PM10 size range is the most relevant with respect to human health with respect to inhalation. However, cadmium in the larger total suspended particulates (TSP), which easily deposit to soils, is also relevant to other exposure pathways from which cadmium can contribute to the body burden. This is of particular relevance for persistent contaminants like cadmium that can build up in the local environment from emitting facilities. A host of studies published in international journals have identified various human health concerns associated with exposure to air-borne cadmium. Cadmium has been directly associated with kidney damage in mammalian species when the intake occurred via ingestion and inhalation. Chronic exposure to airborne cadmium (inhalable or respirable particles) has been linked to increases in lung cancer and the International Agency for Research on Cancer (IARC) has classified cadmium as a Group 1 carcinogen implicating it as “probably carcinogenic to humans”. However, the World Health Organization (WHO) in its recent reanalysis stated that because of the identified and controversial influence of concomitant exposure to arsenic in the epidemiological study, no reliable unit risk can be derived to estimate the excess lifetime risk for lung cancer.

The current Ontario 24-hour Ambient Air Quality Criterion (AAQC) for cadmium is 2 μg/m3. The half-hour point of impingement (POI) standard is 5 μg/m3. The basis for both of the criteria, set in 1974, was protection of human health.

The Ministry of the Environment has reviewed and considered air quality guidelines and standards as well as the derivation approaches used by leading agencies worldwide and advice from Ontario stakeholders. Based on recent evidence and recent reanalysis of studies by the Agency for Toxic Substances and Disease Registry (ATSDR), the World Health Organization (WHO), the European Commission (EC) and stakeholder comments, the Ministry considers the EC’s approach, modified by input from comments received, to be the most appropriate for developing air quality standards. In particular, the non-cancer endpoint of kidney damage, together with the provision of additional protection of human health with respect to carcinogenicity, were considered to provide the most appropriate guideline value on the basis of the studies and plausibility of the mechanisms. Accordingly, the annual cadmium ambient air quality criterion for Ontario is proposed to be 5 ng/m3 of cadmium in total suspended particulates.

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Based on an evaluation of the scientific rationale of air guidelines from leading agencies, an examination of current toxicological research, and comments from stakeholders, the following Air Quality Standards are set for cadmium (CAS# 7440-43-9) and cadmium compounds :

• An annual Ambient Air Quality Criterion (AAQC) of 5 ng/m3 (nanograms per cubic metre of air) for cadmium and cadmium compounds based on kidney effects and carcinogenicity associated with exposure to these compounds ; and

• A 24-hour average AAQC of 25 ng/m3 (nanograms per cubic metre of air) for cadmium and cadmium compounds based on kidney effects and carcinogenicity associated with exposure to these compounds ; and

• A half-hour standard of 75 ng/m3 (nanograms per cubic metre of air) for cadmium and cadmium compounds based on the kidney effects and carcinogenicity associated with exposure to these compounds

These effects-based standards (which include the AAQCs and the corresponding effects-based half hour standards) will be incorporated into Ontario Regulation 419/05: Air Pollution – Local Air Quality (O. Reg. 419/05). The AAQCs (except the annual AAQC) will be incorporated into Schedule 3 of O. Reg. 419/05; the half-hour standard will be incorporated into Schedule 2.

MOE generally proposes a phase-in for new standards or standards that will be more stringent than the current standard or guideline. The phase-in for cadmium and cadmium compounds is set out in O. Reg. 419/05.

Among other things, O. Reg. 419/05 sets out the applicability of standards, appropriate averaging times, phase-in periods, types of air dispersion model and when various sectors are to use these models. There are 3 guidelines that support O. Reg. 419/05. These guidelines are:

• “Guideline for the Implementation of Air Standards in Ontario” (GIASO);

• Air Dispersion Modelling Guideline for Ontario” (ADMGO); and

• “Procedure for Preparing an Emission Summary and Dispersion Modelling Report” (ESDM Procedure).

GIASO outlines a risk-based decision making process to set site specific alternative air standards to deal with implementation barriers (time, technology and economics) associated with the introduction of new/updated/ air standards and new models. The alternative standard setting process is set out in section 32 of O. Reg. 419/05.

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For further information on these guidelines and O. Reg. 419/05, please see the Ministry’s website http://www.ontario.ca/environment and follow the links to local air quality.

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http://www.ontario.ca/environment


Table of Contents

Executive Summary........................................................................................................ i Table of Contents .......................................................................................................... v

1.0 Introduction ......................................................................................................... 1

2.0 General Information............................................................................................ 3 2.1 Physical and Chemical Properties..................................................................... 3 2.2 Production and Uses of Cadmium..................................................................... 3 2.3 Sources and Levels........................................................................................... 3

2.3.1 Natural Sources ......................................................................................... 3

2.3.2 Anthropogenic Sources .............................................................................. 4

2.4 Exposure to Cadmium....................................................................................... 5 3.1 Acute Toxicity .................................................................................................... 8

3.1.1 Inhalation:................................................................................................... 8

3.1.2 Ingestion:.................................................................................................... 9

3.2 Subchronic and Chronic Toxicity ..................................................................... 10 3.3 Developmental and Reproductive Toxicity ...................................................... 11 3.4 Genotoxicity and Mutagenicity......................................................................... 12 3.5 Carcinogenicity................................................................................................ 13 3.6 Environmental Effects ..................................................................................... 16 4.1 Overview ......................................................................................................... 18 4.2 Evaluation of Existing Criteria.......................................................................... 21

4.2.1 Ontario AAQC and half-hour standard ..................................................... 21

4.2.2 Reference Exposure Level based approach ............................................ 21

4.2.3 Carcinogenic Slope Factor based approach ............................................ 21

4.2.4 Recent Approaches.................................................................................. 22

6.0 Responses of Stakeholders to the Rationale Document............................... 27

7.0 Considerations in the Development of an Ambient Air Quality Criterion for Cadmium ...................................................................................................................... 37

8.0 Decision............................................................................................................. 44

9.0 References......................................................................................................... 47

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10.0 Agency-Specific Reviews of Air Quality Guidelines ...................................... 60 10.1 Agency-Specific Summary: Federal Government of the United States ........... 60 10.2 Agency-Specific Summary: World Health Organization ................................. 64 10.3 Agency-Specific Summary: State of California ................................................ 67 10.4 Agency-Specific Summary: New York State................................................... 71 10.5 Agency-Specific Summary: The Commonwealth of Massachusetts................ 74

11.0 Acronyms, Abbreviations and Definitions...................................................... 77


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1.0 Introduction

Ontario regulates air emissions in order to achieve and maintain air quality which is protective of human health and the environment. The Environmental Protection Act (Section 9) requires stationary sources that emit, or have the potential to emit, a contaminant to obtain a Certificate of Approval which outlines the conditions under which the facility can operate.

The Ministry of the Environment uses a combination of regulated point of impingement (POI) standards and guidelines (MOE, 2005) in reviewing Emission Summary and Dispersion Modelling Reports submitted to support a Certificate of Approval application or a Ministry request for a compliance assessment. Ambient Air Quality Criteria form the basis for an air standard or guideline and represent human health or environmental effects-based values, normally set at a level not expected to cause adverse effects based on continuous exposure. As such, factors such as technical feasibility and costs are not considered when establishing AAQCs or the equivalent half hour standards which are derived from the AAQCs using a mathematical scaling factor. The risk based process for alternative standards, as set out in section 32 of O. Reg. 419/05, is the mechanism created to deal with the time, technical and economic issues. The Guideline for the Implementation of Air Standards in Ontario (GIASO) is the supporting document for stakeholders who are interested in more information on alternative standards. For further information on O. Reg. 419/05 and GIASO, please see the Ministry’s website http://www.ene.gov.on.ca/envision/air/regulations/localquality.htm.

Air standards referenced in O. Reg. 419/05 are used for compliance and enforcement. Dispersion modelling, as referenced in the regulation, is used to relate emission rates from a source to resulting concentrations of a particular contaminant. Air standards specified under O. Reg. 419/05 apply to stationary sources only.

In addition to air standards established under O. Reg. 419/05, the Ministry also has a large number of guidelines (including AAQCs). Similar to standards, guidelines are used by the Ministry to assess general air quality and the potential for causing adverse effect (MOE, 2005). Like the air standards specified in O. Reg. 419/05, guidelines (and now AAQCs) are used in reviewing Emission Summary and Dispersion Modelling reports submitted in support of applications for Certificates of Approval, to approve new and modified emission sources or other requirements. Once incorporated into a legal instrument such as a Certificate of Approval, guidelines can become legally binding.

The Ontario Ministry of the Environment continues to develop and/or update air standards for priority toxic contaminants. The Ministry’s Standards Plan, which was released in October 1996 and revised in November 1999 (MOE, 1999; MOEE, 1996), identified candidate substances for which current air standards will be reviewed. The

http://www.ene.gov.on.ca/envision/air/regulations/localquality.htm


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MOE 1999 Standards Plan outlines a multi-step process for developing air quality standards (MOE, 1999). Each standard has undergone a two step consultation process involving postings on the Environmental Registry, under the Environmental Bill of Rights (EBR):

• Information Drafts (Risk assessment/science review only)

• Rationale Documents (Proposed numerical limits)

Cadmium was identified as a priority for review based on its pattern of use in Ontario, and recent toxicological information. The initial step, an Information Draft (MOE, 2004), provided risk assessment information relevant to establishing a standard for a particular substance. This provided stakeholders with the opportunity to critically review the information and provide any additional information they felt should be considered by the Ministry in setting an air quality standard for a particular compound. The Ministry considered comments received on the Information Draft and recommended proposed standards: Ambient Air Quality Criterion (AAQC) and a half hour point of impingement (POI) standard, in a Rationale Document (MOE, 2006) and again solicited comments from stakeholders by posting on the Environmental Registry. After assessing comments on the Rationale Document the Ministry has finalized its work by making a decision on the air quality standards for cadmium and cadmium compounds. This decision, which also highlights key comments from stakeholders on the proposed standards and the responses provided by the MOE, is documented by posting a Decision Notice (and supporting ‘Decision Document’, which provides the rationale for the decision on the air quality standards) onto the Environmental Registry.

In the 1999 Standards Plan, MOE made a commitment to consider time, technical, and economic issues for air standards and develop a risk management framework to address implementation issues. The risk-based framework has been developed and is part of O.Reg. 419/05. The alternative standards setting process is a risk-based process that considers time, technical and economic issues on a site specific basis. For further information on Regulation 419/05 and the process for requesting an alternative site specific air standard, please see the Ministry’s website and follow the links to local air quality.




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2.0 General Information

2.1 Physical and Chemical Properties

Cadmium (atomic symbol Cd) belongs to Group IIB of the Periodic Table of elements. Pure cadmium is a soft and malleable bluish-white metal that appears slightly shiny in its solid form. Cadmium powder is grayish-white in appearance. Cadmium does not have a definable taste or odour. The main cadmium compounds of concern in the environment are cadmium oxide (CdO), cadmium chloride (CdCl2), cadmium sulphate (CdSO4), and cadmium sulphide (CdS). These compounds do not breakdown in the environment as they are relatively stable. The following Table provides some physical properties of cadmium and cadmium compounds:

Table 1: Physical properties of some cadmium and cadmium compounds.

Compound Cadmium Cadmium chloride

Cadmium sulphate

Cadmium sulphide

Cadmium oxide

CAS # 7440-43-9 10108-64-2 10124-36-4 1306-23-6 1306-19-0

Melting Point (EC) 321 568 1000 1750 1559 (sublimes)

Density (g/cm3) 8.64 3.33 4.69 4.83 8.15

Water Solubility negligible Soluble soluble insoluble insoluble

Atomic/Molecular Weight grams/mol

112.41 183.32 208.47 144.47 128.41

2.2 Production and Uses of Cadmium

Cadmium, considered to be a heavy metal, is widely used in the production of nickel-cadmium rechargeable batteries (70%), and as an additive in metal alloys and electronic components (~2%). Cadmium compounds such as cadmium sulphide are used in the manufacture of paint pigments (13%), anti-corrosive metal coatings (8%), and stabilizers in plastics (7%) (www.cadmium.org).

2.3 Sources and Levels

2.3.1 Natural Sources

Cadmium is a naturally occurring metal in the earth's crust. It is commonly found combined with other elements such as oxygen (cadmium oxide), chlorine (cadmium


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chloride), or sulfur (cadmium sulfate, cadmium sulfide). All soils and rocks, including coal, contain cadmium (ATSDR, 1999).

Rock erosion, forest fires, and volcanic eruptions are naturally occurring processes that result in cadmium emissions to the air. Cadmium is found in the atmosphere (0.1-5 ng/m3), crust (0.1 to 0.5 µg/g), marine sediments (circa 1 µg/g), and seawater (circa 0.1 µg/L) (ATSDR, 1999).

2.3.2 Anthropogenic Sources

Due to the natural occurrence of cadmium in almost all zinc, lead and copper containing ores, most mining and refining processes associated with these metals result in cadmium emissions. Zinc ores contain the highest levels of cadmium and are the primary source of cadmium metal. World-wide production of cadmium from refining activities in 1998 was estimated to be 19,900 tonnes(USGS, 1999). In Canada, the majority of the cadmium is produced in Ontario. Natural Resources Canada reported that Ontario produced 600 metric tonnes of cadmium, or about 45% of the national total.

Environmental contamination by cadmium from anthropogenic sources can be attributed solely to industrial activity. Industries associated with the manufacture, use, and disposal of cadmium products, as well as metal refineries processing raw materials containing cadmium in trace quantities are responsible for point-source releases of cadmium. Frequently the products and by-products of these processes enter the environment in large volumes: for example, refining of non-ferrous metals, the production of iron and steel, incineration of waste, and the combustion of fossil fuels (transportation, electricity generation plants, etc.) results in emissions that include cadmium compounds. The use of phosphate fertilizer, the production of cement, and the disposal of sewage sludge and other industrial and domestic wastes leads to an increase in ground and water sources of cadmium.

As a result of the complexity of the environmental life cycle and the great number and variability of the input data (e.g. industries present, differences in cadmium content and speciation in raw materials, differences in technology to recover cadmium, emission of variety of cadmium compounds, etc.), the development of a quantitative inventory of cadmium emissions to the environment poses a difficult task.

NPRI (National Pollutant Release Inventory) data for Ontario for the years 1999-2004, available through the internet (NPRI, 2004), are shown in Table 2. The available data indicates that there is an increase in the emissions of cadmium and cadmium compounds to the air as well as those released to the land and water. The consequence of this is that an increase in air-borne cadmium is highly probable. The category referring to the release to the roads is due to the re-entrainment of dust due to vehicular traffic in the vicinity of the cadmium processing facilities (foundries, smelting, ore processing, etc.).


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Table 2: NPRI summaries for the release of cadmium compounds to the environment, in kilograms, for the years indicated for the Province of Ontario.

Year of Record Media to which Cadmium is Released 1999 2000 2001 2002 2003 2004

Air 4881 7318 7122 8022.65 9915.07 8716.19

Water 498 205 655 500.52 843.64 1954.75

Land n/a n/a n/a 4.20 n/a 275.68

Roads 100 198 201 n/a n/a n/a

TOTAL (kg) 5479 7721 7978 8527.37 10758.71 10946.62

The available NPRI data indicate that due to the lowering of the reporting threshold from 10 tonnes to 50 kg, there is a great increase in the number of facilities reporting cadmium emissions and hence in the spatial distribution of emissions, as well as, an increase in the reported total emissions of cadmium in the province of Ontario. This would suggest that the probability of exposure to cadmium, for the general population, is also expected to increase.

2.4 Exposure to Cadmium

Cadmium is distributed throughout the environment from natural and anthropogenic sources. It can be found in trace levels in the air, most foods, and in the water. As a result, for the general population, exposure to cadmium can result from all exposure routes and pathways. Populations in the vicinity of certain industries (smelting of ore or refining of metals) will be exposed to higher levels of cadmium and the highest exposures to cadmium are known to occur in occupational settings.

The most common species of cadmium found in the environment is cadmium oxide as dust. Cadmium oxide is also the most commonly formed species from smelting and internal combustion processes and is the compound of concern for inhalation exposure. A recent report from the European Commission found that cadmium emitted from combustion processes consisted of both metallic cadmium and cadmium oxide mixed with other metal oxides (European Commission, 2000). Cadmium sulphide and cadmium sulphate were found in dust emissions from a European lead smelting


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operation although metallic cadmium has been found in similar emissions in other parts of the world.

A review of the cadmium levels in PM10 particles in Ontario, as measured by

Environment Canada, suggests that maximum concentration measured in Ontario occur in Toronto with the highest recorded levels of circa 3.4 nanograms per cubic meter averaged over 24 hours. The table below depicts the maximum cadmium concentration in nanograms/m3 in PM10 particulate matter for several urban centers in Ontario. The values provided in the brackets are the maximum levels recorded at the site. The values not in the brackets represent the 98th percentile of the measured levels. That is, the cadmium levels detected at the urban centers was below the value 98 percent of the time.

Table 3: Cadmium levels (ng/m3) in PM10 in major population centers in Ontario. The 98th percentile level and the maximum level found (in brackets) for the given year is shown.

Year Windsor Toronto Hamilton Ottawa

2000 1.39 (1.93) 3.30 (3.44) 1.95 (2.51) 1.97(2.12)

1999 1.16 (1.16) 1.51 (2.79) 1.95 (1.95) 0.95 (0.98)

1998 2.17 (2.17) 2.86 (2.86) 1.72 (1.72) 2.05 (2.55)

1997 1.55 (1.55) 2.15 (2.15) 2.23 (2.23) 0.97 (1.00)

1996 3.45 (3.45) 2.04 (2.38) 2.65 (2.65) 1.01 (1.04)

Personal habits also contribute to cadmium exposure. The inhalation of tobacco smoke results in a significantly higher exposure to cadmium (and many other compounds that are potentially more harmful) via the inhalation route. A study investigating the cadmium content of cigarettes from various locales in the world reported a range from 0.3 to 3.4 µg Cd/g cigarette (Watanabe, T. et al.; 1987). Therefore, smokers are expected to be exposed to higher levels of cadmium via inhalation depending on the level of cigarette consumption in addition to the environmental sources of cadmium.

3.0 Toxicology of Cadmium

Cadmium toxicity has been well documented. Cadmium exposure is known to be associated with both carcinogenic (primarily via inhalation exposure) and non-carcinogenic (primarily via inhalation and ingestion exposures) toxicity. Cadmium can be taken up either by ingestion or inhalation. Although dermal uptake is possible, it is not considered to be a toxicologically significant risk factor except under occupational exposure conditions. With respect to the various exposure scenarios, sub-chronic and


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chronic cadmium inhalation has been associated with cancer and non-cancer end-points of lung cancer and kidney effects, respectively.

In terms of cancer, there is evidence that cadmium is associated with incidence of cancer as is reflected in the classification scheme of various agencies and until more definitive models emerge, cadmium is assumed to cause lung tumors in humans under the “probable carcinogen” label. However, many of the human studies on cadmium induced carcinogenesis are based on occupational exposures which include exposure to other metals. Because of the recently identified and controversial influence of concomitant exposure to arsenic in the key epidemiological studies used, quantitative derivations of a solely carcinogenicity-based standard are not reliable.

Nephrotoxicity (i.e., kidney effects) is the other important toxic endpoint associated with chronic and subchronic exposure to cadmium. Cadmium induced renal toxicity is the most sensitive toxic effect of cadmium: long-term exposure to cadmium results in an irreversible tubular nephropathy which may develop into renal insufficiency. Cadmium ions absorbed by the respiratory and gastrointestinal tracts are stored in the liver in the form of a complex with metallothionein (MT), which is transported by the systemic blood flow to the kidneys. MT is a low-molecular protein capable of binding up to seven cadmium ions per molecule. Cd-MT is efficiently filtered through the glomerular membrane, taken up by renal tubular cells, and rapidly degraded by lysosomes. It is now generally accepted that part of the cadmium liberated escapes renewed binding to MT and reaches subcellular targets causing toxicity. As a result, the re-absorption of low molecular weight proteins (e.g., β2-microglubulin, retinol-binding protein, N-acetylglucosaminidase) is irreversibly impaired, indicating tubular damage, and manifesting itself as proteinuria. Tubular proteinuria is a relatively specific effect of cadmium on the kidneys. At higher levels or longer durations of exposure, increased excretion of high molecular weight proteins occurs, indicating either glomerular damage or severe tubular damage (RIVM, 2001). Generally, although there is no single unifying mechanism, the ability of cadmium to interfere with calcium is a factor common to many of its nephrotoxic effects.

The toxicological description of metals such as cadmium presents an additional interesting regulatory challenge because of recent research and advances in the understanding of mechanism(s)-of-action of the metals. For example, even though nickel, arsenic, cobalt and cadmium are classified as carcinogens, their mutagenic potentials are relatively low. However, these metals appear to disturb or interfere with DNA repair systems through mechanisms not clearly understood (Hartwig, A. and Schwerdtle, T., 2002; Sky-Peck, H. H., 1986). The standard-setting process therefore, may have to consider implications that go beyond the traditional determinants of toxicity classification such as LC50, NOAEL, LOAEL, etc., because simultaneous exposures to these metals could potentiate other compounds that are weakly mutagenic. While these issues are not fully resolved at the present time, they do give guidance in the future to


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the standard-setting process, to consider more mechanistic information than has traditionally been the case.

3.1 Acute Toxicity

The route of exposure and the speciation characteristics of cadmium affect the absorption and distribution to the various target sites. In addition, the particle size can also have an affect on retention of particles containing cadmium compounds and hence affect the absorption and subsequent distribution. The following discussion considers the acute toxicity resulting from exposure to cadmium primarily via inhalation and ingestion.

3.1.1 Inhalation:

The majority of the knowledge of acute toxicity of cadmium by inhalation is based on occupational exposure studies in industries such as battery manufacturing, smelting and refining, soldering and welding, and pigment production. The most common form of airborne cadmium in these settings has been identified as cadmium oxide (CdO) and workers can be exposed to either fumes or dusts.

Studies have shown that death can result from exposure to cadmium dusts and fumes. Although the initial symptoms appear to be mild, pulmonary edema and chemical pneumonitis developed within a few days and death resulted from respiratory failure (Beton, D. C. et al.; 1966; Lucas, P. A. et al.; 1980; Patwardhan, J. R. and Finckh, E. S., 1976; Seidal, K. et al.; 1993). Analysis of the lung tissue suggested that the amount of cadmium per wet weight ranged from 1.5 to 4.7 µg cadmium/ g lung tissue. Analysis of the estimate of exposure suggested that the levels these individuals were exposed to were about 8 mg/m3 (Beton, D. C. et al.; 1966; Lucas, P. A. et al.; 1980; Patwardhan, J. R. and Finckh, E. S., 1976; Seidal, K. et al.; 1993). Beton et al., (1966) estimated that death resulted from approximately a 5-hour exposure to 8600 µg/m3 exposure to cadmium oxide. This level of exposure are only likely under occupational exposure conditions.

Animal studies are generally supportive of these observations. Acute inhalation of CdO containing particles was found to cause histochemical and biochemical changes in the respiratory tissues in rats (Buckley, B. J. and Bassett, D. J., 1987). Their study considered the effects of a single 3-hour exposure of either a 0.5 and 5.3 mg/m3 CdO. In the group exposed to higher levels of CdO, histochemical changes correlated well with two-fold increases in tissue protein and DNA content fifteen days after exposure when compared to unexposed control animals. This group exhibited an increase in noncellular thickening of the interstitium and a continued general hypercellularity in the lungs. The lung tissue in the group exposed to lower levels of cadmium oxide had returned to normal by the fifteenth day post-exposure.


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Rusch et al. (1986) reported that a single 2-hr inhalation exposure to approximately 100 mg/m3 (based on cadmium content) as cadmium carbonate dust, fume, and two insoluble cadmium pigments (cadmium red and cadmium yellow) resulted in the following observations. There was no mortality in the rats exposed to cadmium red or cadmium yellow in the time-frame of the study. In the group exposed to cadmium carbonate, 3 out of 52 rats died, while 25 out of 52 rats exposed to fumes died. Cadmium blood levels from the rats exposed to cadmium carbonate dust and fumes were reported to be greater in comparison to the group exposed to the insoluble cadmium red and cadmium yellow pigments. In terms of the elimination of the cadmium compounds, 80% of the insoluble pigments were cleared via the faeces within 24 hours. Elimination was slower following exposure to the carbonate species and higher levels of cadmium were found in the liver and kidneys. This study would suggest that the toxicity, absorption, distribution, and excretion are dependent on the solubility of the cadmium compound.

Acute inhalation toxicity in humans has been documented. Exposure to high levels of cadmium oxide dusts or fumes has been reported to cause irritation to respiratory tissue. Beton et al. (1966) calculated that an acute exposure of about 8 mg/m3 for 5 hours could result in the immediate symptoms of coughing with an irritation of the throat and mucosa followed by influenza-like symptoms accompanied by cough, chest pain, chills, shivering, and back pains about 4-10 hours post-exposure. However, reliable estimates of cadmium concentrations leading to acute respiratory effects in humans are not currently available.

3.1.2 Ingestion:

Controlled animal studies have shown that cadmium can be acutely toxic if ingested. In rats and mice, the acute oral LD50 for cadmium ranged from 100-300 mg/kg although the lowest dose causing death was 15 mg/kg in the case of Sprague-Daly rats (Borzelleca, JF et al.; 1989). Younger animals appear to be more sensitive to cadmium and have lower reported acute oral LD50 values (Kostial, K. et al.; 1978; Kostial, K. et al.; 1989)

Acute effects in humans following the ingestion of cadmium compounds have been ascertained from observations after suicide attempts and the exposure levels recorded are unlikely to be achieved inadvertently. Intentional ingestion of cadmium (iodide and chloride salts) resulted in symptoms such as fluid loss, edema, and organ destruction. The dosage was estimated to be 25 and 1,840 mg Cd/kg for the iodide and chloride salts, respectively. The time to death was approximately 33 hours with cadmium chloride and seven days with cadmium iodide (Oldiges, H et al.; 1989). Although these circumstances are only likely to be duplicated inadvertently, they are indicative of the acute toxicity of cadmium. The World Health Organization (WHO) has estimated the lethal oral dose to be 350–3500 mg of cadmium (Krajnc, E. I. et al.; 1987).


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3.2 Subchronic and Chronic Toxicity

The route of exposure and speciation of the cadmium compound are critical factors in the determination of sub-chronic and chronic toxicity and the toxicological end-point of exposure. Studies have cited both kidney effects and lung cancer as the end-point from chronic cadmium exposure. Non-carcinogenic effects, such as changes in kidney function, have been observed in animal and human studies. Human studies, on populations occupationally-exposed to cadmium dusts, have also indicated evidence of carcinogenicity.

Two studies, by Buchet et al., (1990) and Jarup et al., (2000), have provided both a robust data-set and the appropriate analysis of the non-cancer effects of chronic cadmium exposure in the general population and a population subset exposed to cadmium emissions from a nearby battery manufacturing facility located in their neighbourhood as well as occupational exposure for many of the people in the community who were employed at this facility. Buchet et al. (1990) study involved 1699 subjects ranging in age from 20-80 years living at two sites in Belgium with known but different levels of environmental cadmium. Urinary cadmium (as total cadmium bound to the protein globulin) was used as the marker of exposure to cadmium. Multiple logistic regression analysis was used to estimate creatinine-controlled urinary cadmium cut-off levels above which at least 10% of the population is expected to have abnormal values of urinary markers (elevated cadmium output in urine) in subjects without diabetes, urinary tract disease, or treatment with analgesics. According to their model, a level of 2.7 µg/24 hours for 5% of the population was estimated to be the threshold level for cadmium related proteinurea and would be expected to occur if the inhalation exposure to cadmium was circa 650 nanograms/m3.

The study by Jarup et al., (2000) involved 1021 subjects who resided in the vicinity of a cadmium battery manufacturing plant; 220 individuals in the sample were occupationally exposed to cadmium as well. The subjects ranged in age from 16-80 years. Multiple logistic regression analysis similar to the approach used in the study by Buchet et al., (1990) led to similar results with a range of 1 - 2 µg cadmium excreted in 24 hours being the abnormal value range using the same dose metrics.

Both of the studies also identified possible sensitive sub-populations as persons with degenerative kidney damage (diabetics, elderly, etc.) and individuals with lower iron stores who may have a slightly higher cadmium uptake.

A study of a population previously exposed to cadmium in soil evaluated the renal function and cancer incidence (Arisawa et al., 2001). A total of 275 individuals in ages ranging from 40-92 years who had resided in a Cd-polluted area located on Tsushima Island, Nagasaki, Japan were evaluated for urinary cadmium levels as well as general mortality and cancer incidence. The study found that renal tubule dysfunction (based on


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increased total cadmium output in the urine) is a predictor of mortality among persons exposed to cadmium in their environment. However, the overall incidence of cancer was not statistically higher among residents in areas with contaminated soils. It is important to note that the study sample was small, and, children and sensitive populations were not considered.

Similar observations were made in an occupational exposure study. Smith et al. (1980) compared two groups on the basis of occupational exposure to cadmium in dusts. A low exposure group of office, laboratory and supervisory personnel (n = 11, average urinary cadmium 13.1 micrograms/L) was compared with a high exposure group of production workers with a long history of work in areas with high airborne cadmium levels (n = 16, average urinary cadmium 45.7 micrograms/L). Inhalation exposure was estimated from personal sampling data. Comparison of the kidney function between the high and low exposure groups found a significant reduction in creatinine output and an increase in the uric acid and beta microglobulin output by the high exposure group. The relationship between urinary cadmium excretion and calculation of the cumulative exposure to airborne cadmium was consistent with the adverse effects of cadmium on the kidney.

3.3 Developmental and Reproductive Toxicity

Studies on developmental and reproductive toxicity are sparse. In animal models, no significant potential for reproductive toxicity is reported. A study from Holland examined some reproductive parameters on cows that grazed in an area with higher than normal cadmium levels (Kreis, I. A. et al.; 1993). The findings suggested that cows from the exposed area required a greater number of insemination attempts to conceive, although the incidence of inter-uterine deaths were not significantly higher in comparison to the control group. The study also found that the incidence of twin births was significantly lower.

Human data on reproductive and developmental effects from cadmium is limited and any results should be treated as preliminary findings due to the lack of controlled studies. In one of the few peer-reviewed studies known, women with higher body burdens of cadmium (determined by urinary cadmium) had babies with smaller birth-weight, independent of smoking habits. However, there was no correlation between cadmium levels in urine and newborn weight (Cresta, L. et al.; 1989).

A study carried out by Salpietro et al., (2002) measured the maternal and cord blood cadmium levels in 45 healthy non-smoking pregnant women who had resided in areas containing higher cadmium levels in the environment (soil and air). The results showed fairly low cadmium levels in maternal blood but did establish a highly significant correlation between maternal and cord blood cadmium concentrations. Based on the finding that cadmium concentrations were of the same order of magnitude in both cord


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and maternal blood, the placenta likely does not prevent the transport of cadmium in blood from the mother to the child. As in other studies, birth weight was inversely correlated with maternal and cord blood cadmium concentrations. The authors suggested that the data could be interpreted to suggest that prenatal exposure to even low cadmium levels might pose a risk for developmental impairment in infants on the basis that cadmium does cross the placenta.

Animal studies have shown similar results. Maternal exposure to subcutaenous cadmium (as a chloride) was found to reduce lung weight and affect pulmonary surfactant development in the fetus (Daston et al., 1982). This could lead to respiratory distress and death in the newborn. Evaluation of fetal lungs (rats) obtained from animals whose mother was exposed to cadmium were examined for protein, DNA, and glycogen. The DNA content of the lungs was found to have decreased in comparison to the control but the ratio of protein/DNA was unaltered. The author suggested that the reduced lung weight was due to hypoplasia and not hypotrophy. Interestingly, the glucose content of the lung tissue was found to be lower in comparison to controls and this may be attributed to the reduced capacity to synthesize pulmonary surfactant prior to birth.

3.4 Genotoxicity and Mutagenicity

Genotoxic effects from inhalation exposure to cadmium alone are not well documented in human studies. There are animal studies that implicate genotoxic effects from acute exposure to inhaled cadmium chloride (circa 1 hour exposure at 80 mg/m3). Mice subjected to cadmium chloride inhalation were found to have genotoxic damage in the cells of several organs such as nasal epithelial cells, lung cells, whole blood cells, liver, kidney, bone marrow, brain and testicle (Valverde, M. et al.; 2000). The study also found correlation between length of exposure, metal concentration in the tissue, and genotoxic damage suggesting that cadmium chloride can induce systemic DNA damage via inhalation exposure.

The literature is unclear whether the DNA damage is consistent with mutagenecity or clastogenecity of cadmium. A subsequent study (Valverde, M. et al.; 2001) examined the DNA damage in cells derived from the liver, kidney and lung of CD-1 male mice after exposure to both lead and cadmium (as a chloride). The study found that inhalation exposure to cadmium (0.08 µg/cm3) induced lipid peroxidation and an increase in free radical levels in the different organs of CD-1 male mice suggesting that oxidative stress might be the causative factor of genotoxicity and carcinogenecity. A study that investigated the mutagenicity of cadmium in hybrid hamster-human mammalian cell assay, found that the carcinogenecity of cadmium could be explained by its mutagenic activity that interferes with the repair of oxidative DNA damage (Filipic, M. and Hei, T. K., 2004).


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A recent study on the marine organism Mytilus edulis (mussel) determined that cadmium was not a direct genotoxic agent in mussel gill cells under both acute and chronic exposure conditions. This was based on the observation that prior exposure to low concentrations of cadmium enhanced the genotoxicity of hydrogen peroxide, a known mutagenic agent within these cells. The genotoxic effect of cadmium was characterized, in this case, as a decrease in the post-treatment DNA repair. Interestingly, the effects of cadmium could be reversed by zinc suggesting that the inhibitory effect of cadmium on DNA repair were likely caused by the displacement of zinc ions from active sites on the repair proteins (Pruski, A. M. and Dixon, D. R., 2002).

Mammalian studies investigating the genotoxic effects of cadmium have been inconsistent. However, a study investigating genotoxic effects in humans has been reported where occupational co-exposures to various metals in air (cadmium, cobalt, and lead) led to the inhibition of DNA repair mechanisms (Hengstler, J. G. et al.; 2003). While the precise mechanism of effect is not known at this point, Valverde et al., (2001) suggest that oxidative stress could be a factor.

Most of the studies cited have used cadmium chloride, a relatively soluble salt of cadmium, and do not propose a mechanism. Irrespective of the mechanism, there is an association between exposure to cadmium and damage to the DNA in the cells of the organ where contact (exposure) occurs.

3.5 Carcinogenicity

Cadmium is classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC, 1993). A Group 1 designation denotes that there is sufficient evidence of carcinogenicity in humans. Compounds could be placed in this category if there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the compound acts through a relevant mechanism of carcinogenicity. Table 4 below provides the classification of cadmium compounds with respect to carcinogenicity by different agencies.

According to the classification schemes used by the various organizations, cadmium is regarded as a carcinogen. Under the IARC classification, cadmium compounds are carcinogenic to humans; the EC regards substances designated as “2" to be considered carcinogenic, while those designated “3" lack the sufficient evidence to be regarded as carcinogens. Under the US EPA classification, compounds labeled “B1" are denoted to be probable human carcinogens based on animal studies but with limited human evidence. In the Health Canada scheme, Group II compounds are classified as “probably carcinogenic to humans”.


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Table 4: Classification scheme of various cadmium compounds by different agencies

Organization Cadmium Species

IARC1 EC2 US EPA3 Health Canada

Cadmium and cadmium compounds

Group 1 Group B1 Group II (inhalation route)

Cadmium chloride Group 2

Cadmium oxide Group 2

Cadmium sulphate Group 2

Cadmium sulphide Group 3

1International Agency for Research on Cancer 2European Commission 3United States Environmental Protection Agency

A literature survey by Collins and Brown (1992) suggests that ingestion of cadmium (oral route) compounds does not lead to a carcinogenic response. Their recommendation is based on meta-analysis of several studies that found that:

1. a database for genotoxicity of cadmium with more negative test results than positive results and with most positive results in in vitro tests, indicating limited potential for genotoxicity;

2. epidemiologic evidence of respiratory tract cancer and prostatic cancer in people occupationally exposed to airborne cadmium but no reliable evidence of gastrointestinal tract cancers in workers; and

3. a large dietary oncogenicity study in rats of cadmium chloride at several dose levels, including a maximally tolerated dose (50 ppm) in males, which showed no increase of tumors due to cadmium ingestion in all of the 19 tissues examined.

Human studies that considered the inhalation route found significant evidence for the carcinogenic potential of cadmium. A 2-fold excess risk of lung cancer was observed in cadmium smelter workers. The cohort consisted of 602 males who had been employed in production work a minimum of 6 months between the years 1940 to1969. The population was followed to the end of 1978. Urinary cadmium data available for 261 workers employed after 1960 suggested a highly exposed population. The authors were able to ascertain that the increased incidence of lung cancer was probably not confounded by the presence of arsenic or due to the smoking habits of the workers due to the amount of data available and the analysis techniques employed (Thun, M. J. et


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al.; 1985). It should be noted that the subjects in this study were exposed to cadmium as a result of their occupation. The general population would not be expected to be exposed to cadmium at these occupational levels (500 µg/m3) for a prolonged period.

Animal studies have established the toxicological effects of chronic cadmium inhalation. Long-term (chronic) inhalation of cadmium chloride (CdCl2) at concentrations as low as 12.6 µg Cd/m3 caused the development of lung tumors in rats (Thidemann et al., 1989).

The development of lung tumors is consistent with another study which looked at the chronic effects of cigarette smoke and cadmium body burden on rats. Gairola and Wagner (1991) carried out a study on mice and rats to determine how cadmium inhaled via cigarette smoke is distributed in the organs. Male C57B1 mice and Sprague-Dawley rats were exposed daily, over a period of 52-60 consecutive weeks, to cigarette smoke. At the end of the exposure period, cadmium levels 5 to 6- and 2 to 3- times greater than levels observed in unexposed controls were detected in the lungs and kidneys of the mice and rats, respectively. Interestingly, increased cadmium levels were not observed in the liver of exposed mice or rats indicating that low-dose chronic inhalation exposure to cigarette smoke leads to highest cadmium accumulation in the lung, followed by the kidney.

Animal studies on carcinogenic potential of inhaled cadmium compounds are well documented and show a strong correlation between inhalation exposure and lung tumours. Cadmium compounds (chloride, oxide, and sulfate, and sulfide) were shown to cause lung tumours in rats under long-term inhalation conditions (Oldiges, H et al.; 1989). This study reported a mortality rate of 75% due to lung tumours after 30 months when the cadmium chloride level was 30 µg/m3. In the control group, no lung tumours were found. Of the group receiving inhalation exposure to cadmium chloride, 18 out of 20 males and 15 of 18 females were found to have primary (malignant) lung tumours. It is interesting to note that a previous study (Takenaka, S. et al.; 1983)) had also shown that male rats exposed to cadmium chloride aerosols for long-term (18 months) developed lung tumours proportional to the dose.

Concerns have been raised about the use of rodent models in extrapolating the incidence of cadmium induced tumours in humans. Maximilien et al. (1992) suggest that the rat may be much more sensitive to the induction of cancer because of the increased retention of poorly soluble compounds. A comparison of the possible dose-effect response in humans, and the dose-response in rats, showed that the shape of the dose-response to cadmium cannot be extrapolated as it can be for other induced cancers. The ability of the cadmium compound to induce tumours in lungs is based on the retention time and solubility (Heinrich, U., 1992). It is likely that the slight differences in the lung tissue of different mammals are a source of variability when comparing species.


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From a regulatory viewpoint, there is evidence that cadmium is associated with incidence of cancer as is reflected in the classification scheme of various agencies and until more definitive models emerge, cadmium is assumed to cause lung tumors in humans under the “probable carcinogen” label. However, it is noted that many of the human studies on cadmium induced carcinogenesis are based on occupational exposures which include exposure to other metals. Furthermore, the concentration to which workers are exposed to the metals is considerably higher than has been observed in the general environment. To this end, a study by Sorahan and Esmen (2004) suggested that the solubility of the cadmium compounds may have a greater influence on carcinogenesis. Therefore, insoluble cadmium species would likely not lead to carcinogenesis based on the analysis of lung cancer mortality in workers at a nickel-cadmium battery manufacturing plant.

3.6 Environmental Effects

Cadmium can be taken up by plants, terrestrial animals, and various aquatic species. Ecotoxicologic studies indicate that there is wide variability in uptake, storage and physiological effects of cadmium.

Toxic impacts observed on one species may be the result of biomagnification through the food chains. As a result, the effects may include changes in the health, longevity, and reproduction of certain species. Ecological risk assessments are more complex to interpret than human health risk assessment because of the different levels of organization.

In general, the environmental and ecological effects due to the increase in cadmium concentrations (above normal background levels prior to anthropogenic activities) involves the consideration of a number of receptors ranging from microbial species in the soil and water to forest ecosystems encompassing flora and fauna.

The impact of increased soil cadmium was found to affect various growth parameters of microbial colonies (Kozdroj, J., 2001). While cadmium did initially reduce the number of bacteria, over time, the metal-tolerant bacterial colonies did increase. On the other hand, bacteria have also been implicated in the remediation of metal contaminated soil (Bruins, M. R. et al.; 2000). Their study found that a common bacterium (Pseudomonas pickettii) found in soil, groundwater, and in fauna, is resistant to most heavy metals and is capable of carrying out normal homeostasis under various conditions. Microbial impacts due to increased cadmium concentration are difficult to characterize because of the adaptability of many micororganisms (see Roane, T. M. and I. L. Pepper (1999) for one example).

The uptake of cadmium by plants is also of concern in the translocation of cadmium from soil to the biota. Plants are observed to take-up heavy metals from the soil and


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redistribute it in the roots, shoots, and the leaves. In most cases, the roots have the greatest content of cadmium followed by the shoots and the leaves(Koeppe, D. E, 1977). While the adverse effects of cadmium on edible plants have been linked to reduced yields, there is the concern that consumption of these plants by humans or animals could have an adverse impact. Most studies indicate that very little accumulates in the fruits but that the leafy plants such as spinach and lettuce could have higher levels of all metals that are found in the soil.

Cadmium has also been shown to be toxic to woody plants. A study carried out in the mid-‘70s demonstrated a reduction in the growth of silver maple when treated with cadmium chloride. The mechanism was believed to be related to the deterioration of the xylem tissue by cadmium (Lamoreaux, R. J. and Chaney, W. R., 1977). Watmough and Hutchinson (2003) carried out a controlled experiment where radioactive lead and cadmium applied to the exterior bark of sugar maple (Acer saccharum Marsh.), white ash (Fraxinus americana L.) and white pine (Pinus strobus L.). Measurements indicated that both cadmium and lead could translocate to the xylem tissue. While a majority of the applied isotope was recovered (over 94%) from the bark tissue, a very small amount entered the outer rings in all three of the varieties studied. This observation suggests that cadmium (and lead) compounds that are deposited on the surface of trees do not necessarily have harmful effects.

The impact of cadmium deposition on freshwater lakes has also been studied. Croteau et al. (2002) detected an increase in cadmium levels in the aquatic food-web over a thirteen year period even with a reduction in the emissions of various metals from nearby smelters. Their study measured the total cadmium in freshwater lakes in the vicinity of two metal smelters in Canada to determine whether reduction in airborne cadmium emissions would result in lower cadmium content in the aquatic food-web. They concluded that even though cadmium in the water did show reduced cadmium levels over the time period of the study, the cadmium content in animals actually increased in some of the lakes. The reason for this observation was postulated to be a reduction in the acidity of the lake water which results in lower amount of protons leading to an increased cadmium uptake.

Glover and Hogstrand (2003) studied the effects of dissolved metals on intestinal zinc uptake in freshwater rainbow trout under controlled conditions. Cadmium was found to inhibit the uptake of zinc, an essential metal, thus posing a health risk to the trout. The mechanism of inhibition is probably related to the increase in the mucus secretion in the intestine in response to the cadmium as well as having a competing cation.

In conclusion, there is adequate evidence in the peer-reviewed literature that points to adverse effects of cadmium on various receptors in the ecosystem and reaffirms the need to control environmental releases of cadmium.


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4.0 Review of Existing Air Quality Criteria

4.1 Overview

The current Ontario 24-hour Ambient Air Quality Criterion (AAQC) for cadmium is 2 μg/m3. The half-hour point of impingement (POI) interim standard is 5 μg/m3. The basis for both of the criteria, set in 1974, was protection of human health.

In revising the air quality standards for Ontario, the Ministry of the Environment is considering risk assessments and the scientific rationale of guidelines and criteria used by other environmental protection agencies. This report reviewed the scientific basis for air quality guidelines and criteria developed by the US Environmental Protection Agency (EPA), the World Health Organization, the State of California, the State of New York, the European Commission, and the Commonwealth of Massachusetts. These agencies are discussed because of the slightly different approach each used in their development of cadmium guideline or standard values. Agency-specific summaries of information concerning air quality guidelines for cadmium are presented in Section 10.0, of the Appendices of this report.

The rationale used by Health Canada to set an adverse effects level differs from that used by the US EPA and will be outlined briefly. The main reason for contrasting these two agencies is to outline the differences in the outcome of a guideline value on the basis of the initial assumptions and the studies used.

A brief summary of available criteria is presented in Table 5. In reviewing the air quality guidelines and exposure limits presented in Table 5, it should be noted that the Ministry of the Environment typically uses a factor of 5 to convert from guidelines based on annual average concentrations to 24-hour average concentrations and a factor of 3 to convert from guidelines based on 24-hour average concentrations to half-hour point-of-impingement limits. These factors are derived from empirical measurements and are selected to ensure that if the short-term limit is met, air quality guidelines based on longer-term exposures will not be exceeded. However, depending on the health end-point being considered, other conversion factors may also be employed.

Some agencies have developed specific guideline and standard values for cadmium compounds (i.e., cadmium salts). Generally, these numbers have been developed from an industrial setting and are based on the carcinogenic potential.


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Table 5: Summary of Existing Air Quality Guidelines [1] for Cadmium

Agency Guideline Value Basis of Guideline Date[2] Comments

5 µg/m3 (½-hour average, POI)

Human Health 1974

Ontario (MOE) 2 µg/m3 (24-hour, AAQC)

Human Health 1974

Based on extrapolation to low concentration from occupational exposure studies.

Canada (CEPA) TC0.05 of 5.1 μg/m3

(Not a guideline value but an assessment of various studies)

Human Health (Cadmium Chloride). This corresponds to a concentration of 0.1 ng/m3 r for a risk of 10-6. Calculated by dividing TC0.05 by 50,000.

1994 This substance is listed on the Priority Substance List 1. Please see glossary for definition of TC.

Quebec 6 x 10-4 µg/m3

(Annual) Adopted from US EPA inhalation cancer risk value shown below.

2001 Air concentration associated with an increased risk of 1 in 106

US EPA (IRIS) 6 x 10-4 µg/m3 (Risk of 10-6)

6 x 10-3 µg/m3 (Risk of 10-5) (Both values based on Annual)

Human Health - Cancer

Unit risk value of 1.8×10-3 (µg/m3)-1 used to derive the annual value.

1992 Air concentration associated with an increased risk of 1 in 106 and 1 in 105

0.02 µg/m3 Kidney and respiratory effects 2000 Chronic inhalation RELCalifornia (CAPCOA)

0.00024 µg/m3 Cancer based on unit risk of 4.2×10-3 tumours per µg/m3.

1994 Inhalation cancer risk value

3 ng/m3 (24-hour) Human Health 1995 Cancer Massachusetts (DEP)

1 ng/m3 (annual) Human Health 1995 Cancer

Michigan (DEQ) 0.00056 µg/m3

(annual IRSL) Based on US EPA inhalation cancer risk value

1992 10-6 risk of cancer

New York (DEC) 5 x 10-4 µg/m3

(annual) Human Health 1995 10-6 risk of cancer

0.1 µg/m3 (short-term ESL)

Human Health 2003 Occupational Exposure

Texas (TNRCC)

0.01 µg/m3 (long-term ESL)

Human Health 2003

WHO 5 x 10-3 µg/m3

(annual guideline value)

Kidney effects 1999 Non-cancer


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Agency Guideline Value Basis of Guideline Date[2] Comments

European Commission

5 x 10-3 µg/m3 [total cadmium in airborne dust] (annual guideline value)

Kidney effects (and also appropriate level of protection from cancer risk)

2000 Non-cancer (and also appropriate level of protection from cancer risk)

1Guidelines in this table can refer to: guidelines, risk-specific concentrations based on cancer potencies, and non-cancer-based reference concentrations. 2Date refers to when the health-based guideline background report or original legislative initiative was issued. The sources were the respective agency documents. For the US EPA, date refers to when the latest review of the RfC was conducted, if applicable, or the date the IRIS database was accessed, in the case where no RfC has been developed.

Most of the state agencies in the US have based their regulatory values for cadmium-in-air on the basis of the carcinogenic unit risk developed by the US EPA in 1992. The unit risk established by the US EPA was 1.8 × 10-3(μg/m3)-1. This would translate to cadmium levels of circa 0.6 ng/m3 over lifetime to which a person could be continuously exposed to with a theoretical 1 in a million chance of developing cancer. Many of the US State agencies with a risk management policy based on a 1 in one million cancer risk use the value of 0.56 ng/m3 as their annual regulatory value.

The approach used by Health Canada (CEPA, 1994) is different in that a tumorigenic concentration at 5.0 % increase in incidence or mortality (TC0.05 – see glossary) was calculated from a long-term rat study of Takenaka et al. (1983). No consideration was given to epidemiological studies of occupationally exposed workers due to confounding issues caused by other contaminants. The TC0.05 for cadmium chloride was calculated by fitting the multistage model to the observed frequency of the detection in lung tumors reported in Takenaka et al. (1983) and Oldiges et al., (1984) studies. The model yielded a TC0.05 of 2.9 μg of Cd/m3 for the rat. This value, based on an exposure of 23 hours/day for 72 weeks, was then converted to an equivalent concentration in humans using standard values for the breathing volumes and body weights of rats and humans. After adjusting the toxicity values derived in the rat study to humans, a concentration leading to a tumorigenic effect in humans was estimated to be 5.1 µg/m3. Adjusting this value from a tumor incidence of 5 per 100 to 1 per million will yield a concentration of approximately 0.1 ng/m3. While this value is about one-fifth of the value predicted from the study data and analysis method used by the US EPA from human studies, in reality are similar when the solubility of cadmium oxide (lower solubility) is compared to the relatively soluble cadmium chloride.


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4.2 Evaluation of Existing Criteria

A review of the existing criteria for most of the jurisdictions suggests that the older air quality standards are based on occupational exposure limits adjusted for the general population using a safety factor of 100, as is the case in Ontario. Other jurisdictions use different carcinogenic unit risk values but the same approach as is the case for the State of California (discussed below). More recent approaches relied on non-carcinogenic effects on kidney function in the development of their criteria. More recent approaches relied on non-carcinogenic effects on kidney function in the development of their criteria. This was prompted primarily by the controversy related to confounding factors from other pollutants (i.e., arsenic) in the cadmium occupational studies.

4.2.1 Ontario AAQC and half-hour standard

The existing standards of 2 µg/m3 over a 24-hour period (24-hour AAQC) and 5 µg/m3 half-hour standard are based on human health considerations based on occupational exposures. The 24-hour AAQC was based on 1/100th of the TLV (threshold limit value) based on occupational exposures. There was concern for the accumulative effects of cadmium on kidney damage resulting in proteinuria, hypertension, and emphysema. The carcinogenic risk from cadmium exposure was not considered in the setting of the standard.

4.2.2 Reference Exposure Level based approach

A number of agencies have based their 8-hour exposure values on the basis of the occupational exposure estimates based on kidney effects. California has also derived a chronic REL (chronic reference exposure limit) on the basis of kidney effects. The derivation of this reference exposure level was based on a study comparing the exposed vs. non-exposed males in the LOAEL, as well as a similar cohort [female] in the no observed adverse effect level (NOAEL). The critical effects that this study considered were the detection of protein-bound cadmium in the urine. The observed NOAEL was determined to be 0.5 µg/m3. Using an uncertainty factor of 10 for intraspecies variability (sensitive population) and a subchronic uncertainty factor of 3, the inhalation reference exposure level was calculated to be [0.5/ (300)] µg/m3, and rounded up to 0.02 µg/m3.

4.2.3 Carcinogenic Slope Factor based approach

The US EPA in 1991 and the State of California in 1994 have developed the carcinogenic unit risk values for cadmium of 1.8x10-3 and 4.2x10-3 per µg/m3, respectively, based on the study by Thun et al., 1985 with different uncertainty factors applied and assumptions used. Based on the carcinogenic unit risk value the State of California derive a value for cadmium-in-air to be 0.24 ng/m3, which is more


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conservative value than the US EPA value at 0.6 ng/m3. Both estimates for continuous exposure to cadmium-in-air could result in one additional case of cancer per one-million population. The US EPA, however, noted (see Section 10.1, this document), in discussing the Thun et. al., (1985) study, that “because there was a lack of clear-cut evidence of a causal relationship attributable to the cadmium exposure only, this study is considered to supply limited evidence of human carcinogenicity”.

Other agencies began to identify concerns with the carcinogenicity-based approach. A recent review of cadmium by the ATSDR (1999) concluded that the analysis presented in the Thun et al., (1985) study did not account for the confounding factors of smoking and concomitant exposure to arsenic dusts. It was noted that the Thun et al., (1985) study was based on a cohort from a cadmium recovery plant. A study using workers from a cadmium alloy manufacturing plant in England found that cadmium oxide fumes increased the risk of chronic non-malignant diseases of the respiratory tract, but did not find that the data supported lung cancer associated mortality (Sorahan, T. et al.; 1995). A subsequent reanalysis using cumulative exposure estimates adjusted for detailed job histories indicated that lung cancer mortality was not associated with cadmium exposure alone (Sorahan, T. and Lancashire, R. J., 1997). It was found that the concomitant exposure to arsenic trioxide was likely responsible for cadmium-associated mortality. As a result, setting a cadmium-in-air standard on the basis of carcinogenicity only, is not reliable.

4.2.4 Recent Approaches

Because of the identified and controversial influence of concomitant exposure to arsenic in the key epidemiological study, which was used by various agencies previously to develop unit risk factors, new non-cancer based approaches to air guidelines have been developed by the following two agencies.

As noted below, both the WHO and the European Commission (EC) recognized that the main metabolic feature of cadmium is the long biological half-life leading to long retention time of the metal in the body. More than 90 percent of cadmium is found in blood cells in the human body. The cadmium level in the blood is less than 0.5 ug/100 ml in the absence of occupational exposure to cadmium. Interestingly, newborns are essentially free of cadmium. This indicates that cadmium accumulates over time.

The two main sites for cadmium accumulation are the liver and the kidney. In keeping with this observation, these agencies based their cadmium guideline value primarily on the accumulative effect of cadmium in the kidney. However, the EC noted that their recommended guideline provides also an appropriate level of protection from cancer risk due to exposure to cadmium. The studies cited (Roels et al., 1989, 1991, and 1993; Lauwerys et al., 1974 ) considered the relationship between urinary cadmium and the cadmium concentration in the renal cortex of workers occupationally exposed to cadmium as well as other metals. It was found that the case for kidney effects was


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scientifically defensible and was used to base exposure calculations on which an annual average limit could be derived.

4.2.4.1 World Health Organization (WHO)

The WHO (World Health Organization, 2000), in its rationale for cadmium air guidelines, stated that because of the identified and controversial influence of concomitant exposure to arsenic in the epidemiological study of Thun et. al., (1985), no reliable carcinogenic unit risk can be derived to estimate the excess lifetime risk for lung cancer.

With respect to the risk of lung cancer, the WHO discussed the two risk estimates that have been made, one based on long-term rat bioassay data (Takenaka, S. et al.; 1983) and the other on epidemiological data (Thun, M. J. et al.; 1985). Modelling of these data yielded risk estimates that did not agree. The Takenaka data yielded a unit risk of 9.2 x 10-2 (µg/m3)-1; the human data yielded a unit risk of 1.8 x 10-3 (µg/m3)-1. The WHO considers the use of human data as more reliable because of species variation in response. They note further that there is evidence from recent studies (Sorahan, T. and Lancashire, R. J., 1997), that the unit risk of 1.8 x 10-3 (µg/m3)-1, based on the Thun et al., (1985) study, as derived by the US EPA also, might be substantially overestimated owing to confounding by concomitant exposure to arsenic.

Therefore, the WHO based its human health risk assessment on adverse effects on the kidney resulting in proteinuria associated with proximal tubular dysfunction (i.e., tubular proteinuria).

Pooled data from seven epidemiological studies (Thun, M. J. et al.; 1991) were examined for the relation between renal tubular proteinuria and cumulative (i.e., multi-year) cadmium exposure. It showed that the prevalence of tubular dysfunction (background level being 2.4%) increases sharply at cumulative exposure of more than 500 µg/m3-years (i.e., 8.8% at 400 µg/m3-years, 50% at 1000 µg/m3-years and >80% at more than 4500 µg/m3-years). The ‘µg/m3-years’ express the cumulative exposure acquired by a worker over a 45-year working lifespan. Some studies within the pooled data also suggest that a proportion of workers with cumulative exposures of 100-400 µg/m3-years might develop tubular dysfunction (prevalence increasing from 2.4% to 8.8%, increase above background from 200 µg/m3-years). From these studies, the authors (Thun, M. J. et al.; 1991) concluded that the prevalence of renal dysfunction may increase at cumulative exposures between 100 and 499 µg/m3-years, but that it was impossible to identify a no-effect level with certainty given the limitations of the data available (i.e., limited number of subjects, methodological differences, inaccuracies in exposure data). For the workplace, to prevent tubular dysfunction, the authors (Thun, M. J. et al.; 1991) recommended an 8-hour permissible exposure limit of 5 µg/m3 corresponding to a cumulative exposure of 225 µg/m3-years during 45 years of work.


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These estimates agree well with that derived from a kinetic (i.e., metabolic) model (Kjellstrom, T and Nordberg, G. F., 1985), which predicted that the critical concentration of 200 mg/kg in the renal cortex will be reached in 10% and 1% of exposed workers after a cumulative exposure of 500 (i.e., 10 years of exposure to 50 µg/m3) and 160 µg/m3-years (i.e., 10 years of exposure to 16 µg/m3), respectively.

Based on these considerations, the WHO adopted the lowest estimate of 100 µg/m3-years (i.e., from the range of 100 and 499 µg/m3-years above, for an 8-hour exposure, cumulated over 45 years) as the critical cumulative exposure to airborne cadmium. They note further that this is the lowest estimate of the cumulative exposure to airborne cadmium in industrial workers leading to increased risk of renal dysfunction or lung cancer. This lowest estimate corresponds to 2.2 µg/m3, 8 hr time-weighted average occupational exposure over 45 years (i.e., 100 µg/m3-years ÷ 45 = 2.2 µg/m3). Converting this to lifetime average exposure (i.e., 2.2 µg/m3 x 8/24 x 240/365 x 45/70 = 0.3 µg/m3) of the general population (i.e., non-occupational) gives 0.3 µg/m3.

The final recommended WHO air guideline is based on two additional considerations. First, it was noted that existing levels of cadmium in the air of most urban and industrial areas are around one-fiftieth of 0.3 µg/m3. Second, because adverse renal effects were found in areas contaminated by past emissions of cadmium, a final recommended level of 5 ng/m3 cadmium was established to prevent significant increases of cadmium in agricultural soils beyond current levels which would increase the body burden of cadmium in future generations due to dietary intake.

The WHO approach implicitly incorporates an additional uncertainty factor of 60 to the initially derived renal dysfunction-based health value of 300 ng/m3 from the epidemiological studies and further aims to minimize cadmium deposition to agricultural soils, thus limiting an increase in exposure including future dietary intake.

4.2.4.2 European Commission (EC)

The EC (2000) recently developed guidelines for cadmium via a multi-national expert group. The assessment considered both carcinogenic and non-carcinogenic effects.

With respect to lung cancer, similarly to the WHO, they have considered both animal and occupationally-based epidemiological studies. It was determined that the weight-of- evidence did not indicate that carcinogenicity was linked to cadmium exposures alone but was confounded by arsenic exposure (e.g., Sorahan and Lancashire, 1997). The observation that led to this conclusion was that the results of cadmium-induced genotoxicity were inconclusive; this would invalidate a reliable linear extrapolation to a low level exposure, typically expected in the environment, and result in an overestimate of the risk.


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The EC expert group therefore considered the non-carcinogenic effects on the kidney to be the critical effect, with respect to long-term occupational or environmental inhalation exposure to cadmium. Cadmium-induced nephropathy is characterized by an increased secretion of low molecular weight proteins, amino acids and other low molecular weight components in urine due to reduced re-absorption in the proximal renal tubules.

Since knowledge on cadmium induced nephropathy is based on occupational studies, the EC expert group considered the discussion of the WHO on the key occupational exposure studies (i.e., pooled data from seven studies, summarized by Thun et. al., 1991 and discussed above in the WHO’s rationale) which identified a critical cumulative dose of 100 µg/m3-years for the occurrence of renal effects. In addition, they considered that if one takes into account the ratios between PM5 (particulate matter at < 5 μm which is easily inhalable) and TSP (total suspended particulate matter, not all inhalable but which was the basis of the cadmium measurements) provided by Lauwerys (1974) for several workplaces, the cumulative exposure levels in the studies used by Thun et al (1991) may in fact have been lower. This would further support the WHO’s use of the lower bound of the range discussed by Thun (1991).

Therefore, they proposed that the starting point in deriving a limit value (i.e., air guideline) for non-cancer renal dysfunction should be a LOAEL, equivalent to an accumulated occupational exposure of 100 µg/m3-years. Thus, the workplace exposure level must be converted into an equivalent continuous lifetime exposure in order to derive a limit value for the general population. This was done by extrapolating the occupational LOAEL from 8 hours to 24 hours, from 225 working days to 365 days and distributed over an average human lifetime of 75 years (100 x 8/24 x 225/365 x 1/75 = 270 ng/m3), resulting in 270 ng/m3 as the LOAEL for continuous lifetime exposure.

Applying an uncertainty factor of 5 for LOAEL to NOAEL extrapolation and 10 for inter-individual variability, a chronic exposure of 5 ng/m3 (annual mean) was calculated to be the recommended guideline value. In addition to the direct effect of inhalation exposure on human health, the EC also considered exposure through indirect means such as the deposition of cadmium-containing dusts on soil and plants, the transfer of cadmium to the food chain via deposition on agricultural crops, and, via dermal contact and ingestion of soil. Therefore, the air quality guideline is also intended to minimize these indirect impacts of airborne cadmium.

In summary, the majority of the expert group was of the opinion, that an annual mean concentration level of 5 ng/m3 as derived from non-cancer effects provides also an appropriate level of protection from cancer risk due to exposure to cadmium.


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5.0 Responses of Stakeholders to the Information Draft

In June 2004, the Ministry posted an Information Draft document for cadmium and cadmium compounds, for air standards development under the Standards Plan (MOE, 1999; MOEE, 1996) to the Environmental Registry. The Ministry requested stakeholder input regarding the approach used by other agencies, the evidence of cadmium affecting the efficiency of DNA repair systems, other studies which may need to be considered in developing a standard for cadmium-in-air, and whether the appropriate species of cadmium has been used in developing the standard.

During the consultation period the Ministry received 6 submissions from various stakeholders regarding the draft document for cadmium and its compounds. Representatives of the mining industry (2), automotive industry (2) and two industry associations (mining and power generation) submitted comments. The stakeholders raised concerns over the use of cancer-based criteria on which to set an air standard in Ontario; the data for the non-cancer endpoint of kidney damage was suggested to be the most appropriate basis from which an ambient air quality criteria could be derived. The concerns raised by the stakeholders were based on their reviews of the scientific criteria documents published by other agencies (i.e., World Health Organization, European Union, and ATSDR).

Specifically, the stakeholders were cautious in the interpretation of the effect of cadmium on the DNA repair systems. The general consensus was that this research is in an early stage and does not provide conclusive evidence on which a legally enforceable standard can be based. There was general agreement that the appropriate species of cadmium was used on which a standard should be based. Some of the stakeholders identified a number of studies which should be cited in this document. The Ministry reviewed these documents and included those which were relevant to address the stakeholder comments.

Several general science and policy issues, for the overall air standards process, were also identified by stakeholders. For example, stakeholders requested clarification on the appropriate use of the averaging time for exposure. This was identified as being of importance when using cancer-based end-points to set standards as the cancer slope factors or unit risk factors are based on a continuous exposure over a lifetime.


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6.0 Responses of Stakeholders to the Rationale Document

In June, 2006, the Ministry posted to the Environmental Registry a document titled “Rationale for the Development of Ontario Air Standards for Cadmium and Cadmium Compounds” and requested public comments over a period of 91 days. The Ministry received comments from eight stakeholders. Highlights from these comments are summarized below.

Comments Specific to Cadmium and Cadmium Compounds:

Comment: Several studies were cited with comments that identified different factors, essentially confounding factors, which can potentially affect cadmium impacts on the kidney.

A key limitation of the EC guideline is that it is based exclusively on occupational studies where there may have been concomitant exposure to arsenic and potentially other metals that could potentiate the observed nephrotoxicity. A recent study in mice by Liu et al. (2000) showed that although chronic exposure to cadmium produced greater renal toxicity than arsenic alone, the combination (i.e., a mixture) of cadmium and arsenic resulted in greater renal injury than by either of the two individual inorganics alone, suggesting that arsenic may “potentiate” cadmium nephrotoxicity.

Nordberg et al. (2005) concluded that changes in biomarkers of renal dysfunction resulting from arsenic and cadmium exposure give support to the idea that co-exposure to these metals results in more pronounced renal damage than exposure to each of the elements alone, again suggesting that arsenic can potentiate the toxicity of cadmium. It is noted that all of the occupational cohorts identified in the Thun et al. (1991) study, used to support the exposure guideline developed by the EC, have the potential of co-exposure to arsenic or other metals. Thus, the combined exposure to cadmium and arsenic (and possibly other metals), which may have exacerbated nephrotoxicity cannot be discounted.

Based on the above and given the magnitude of the change associated with the proposed AAQC for cadmium, the health-based standards should not be based on the European Commission (EC) guideline. The primary concern with the approach taken by the EC is the reliance on the work of Thun et al. (1991) which did not account for concomitant exposure to arsenic and potentially other metals. Animal and human studies have shown that arsenic can potentiate the nephrotoxicity of cadmium.

Response: The European Commissions (EC) guideline uses the key paper by Thun et al., (1991) that related occupational cumulative air exposures of cadmium to prevalence


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of adverse kidney effect. It is reasonable to assume that the study populations that were used within this meta-analysis may have been concomitantly exposed to arsenic and other metals. However, the EC has relied on this human epidemiological data and have appropriately correlated the physiological markers of kidney dysfunction to cadmium exposure. Confounding variables in epidemiological studies are always limiting, thus preventing conclusive statements on causality. However, it is the MOE’s opinion that the exposure guideline developed by the EC based on the analysis of Thun et al. (1991) is appropriate; however, we also agree that we can not discount the effects of confounders.

More specifically, as identified by the stakeholders, the co-exposure to arsenic as a “potentiator” of the renal toxicity caused by cadmium has been suggested in a mouse study (Liu, J. et al.; 2000) and in an epidemiological study (Nordberg, G. F. et al.; 2005), however at this time it is not possible to quantify the level of interaction that this may have. No mechanistic information was found to lend support to the role of arsenic as a confounder of cadmium-mediated renal dysfunction. In fact, ATSDR’s (Draft, 2005) recent toxicological profile for arsenic suggests that animal studies indicate that the kidney is not a major target organ for inorganic arsenic and that kidney effects are unlikely to be of concern except for secondary effects to fluid imbalances or cardiovascular injury. Furthermore, while Liu et al. (2000) did investigate the effect of cadmium and arsenic alone or combined, the study fails to analyze the statistical significance of the combined treatment compared to individual treatments, thus limiting the conclusions made in the study.

Comment: Several reasons are suggested why the apparent urgency behind the extremely low EC and WHO AQGs (Air Quality Guidelines) is not quite as justified as previously thought. In a recent Canadian study (Benedetti, J. L. et al.; 1999), smoking was found to be the most important contributor to kidney cadmium levels, with a 5-fold increment in cadmium in smokers relative to non-smokers. In Europe, Cd emissions have been reduced in recent years (EC, 2000), and recent Scandinavian studies of kidney Cd in biopsy and autopsy samples (Barregard, L. et al.; 1999; Friis, L. et al.; 1998) have shown that Cd concentrations in adult kidneys have dropped since the 1970s.

Response: Although smoking can be a significant contributor to cadmium exposure and increases the risk of kidney disease by 2-3 times (Jarup, L. et al.; 1998), exposure from airborne cadmium can be significant for those living close to cadmium emitting facilities - point sources (Hellstrom, L. et al.; 2007; Jarup, L. et al.; 1995). Exposure to cadmium from airborne sources is also more significant in non-smokers including children. Furthermore, while the European studies (Barregard, L. et al.; 1999; Friis, L. et al.; 1998) have observed a drop in cadmium concentrations in adult kidneys since the 1970’s and attributed these observations to decreased cadmium emissions, no


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conclusive data were identified for the Ontario situation. In fact, as part of the 2004 NPRI (National Pollution Release Inventory) data for the years 1999-2004, the available data indicate that due to the lowering of the reporting threshold from 10 tonnes to 50 kg, there is a great increase in the number of facilities reporting cadmium emissions, as well as, an increase in the reported total emissions of cadmium in the province of Ontario (Discussed in Section 2.3.2). However, in the U.S. (National Health and Nutrition Examination Survey [NHANES] III, 2005) as part of a national surveillance program, a decreasing trend is observed in cadmium urine levels. No information was identified to either support or refute a similar decreasing trend for Ontarians; however, this does not preclude the MOE from proceeding to develop an updated science based air standard for cadmium. The importance of point-sources of exposures are also discussed as part of a particle size application of the standard.

Comment: The Ministry should examine the final U.S. EPA risk assessment for cadmium, when available, prior to establishing standards, given the use of more recent data (Buchet, J. P. et al.; 1990; Suwazono, Y. et al.; 2006) and the availability of a benchmark dose approach (BMD) for defining the lower bound of effects.

The US EPA chose the study of Buchet et al. (1990) as the critical study for the purposes of establishing a reference concentration (RfC) for cadmium. In this study, the authors derived a NOAEL of 650 ng/m3, which is considerably higher than the NOAEL derived by the EC who used the study of Thun et al. (1991). The draft US EPA methodology applies very few uncertainty factors implying that the EC guideline value may be overly conservative.

More recently, Suwazono et al. (2006) derived a benchmark dose for cadmium induced renal effects. The study was conducted using cohorts that were environmentally exposed, as opposed to occupationally, thus avoiding the potential issues associated with the study of Thun et al. (1991). Given the uncertainties associated with establishing a NOAEL based on previous studies, the study by Suwazono et al. (2006) may be particularly useful fro the purposes of deriving an air standard for cadmium.

The uncertainties associated with the Thun et al. studies (1985, 1991) and the fact that the draft assessment conducted by the US EPA suggests that the EC’s approach is overly conservative, warrant re-examination of the rationale for the proposed health-based AAQC for cadmium.

A related comment from another stakeholder notes that the model-based approach developed by the US EPA and cited by the EC (2000) should be evaluated for consideration in the development of the standards. It appears that this approach has not been reviewed by MOE, but could provide valuable guidance in deriving relevant standards. Since this study includes the effects of exposure of the general population,


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the results could be more relevant than extrapolation from occupationally exposed groups that form the basis of the studies used by the EC and MOE.

Response:

a) The U.S. EPA risk assessment for Cadmium in the first comment and the ‘model-based approach’ developed by the US EPA in the second related comment are the same and separate from the very recent Suwazono et. al.,(2006) study (see part ‘b’ of response), which was not included in the U.S. EPA risk assessment.

The U.S. EPA risk assessment appeared on EPA’s IRIS website as an ‘External Review Draft’ in March 1999. It was never finalized and currently IRIS refers to Cadmium as ‘This chemical is being reassessed under the IRIS Program’ the date being 01/02/1998. In view of this incomplete status, MOE cannot take this into consideration, nor comment on it formally. However, a few observations can be made:

• The EC expert group, when developing the EC guideline in 2000, commented briefly on EPA’s ‘External Review Draft’ which was released in 1999. They did not support EPA’s assumption that the 650 ng/m3 can be considered a NOAEL and felt that uncertainty factors in two areas should be used when deriving the reference concentrations.

• The EPA risk assessment was addressing kidney effects and carcinogenic effects separately, with much lower levels than 650 ng/m3 being proposed, to address carcinogenicity. In contrast, the EC guideline and the MOE proposed standard, was such that the standard, derived from non-cancer effects, effectively also provided a level of protection from cancer risk due to exposure to cadmium.

b) The recent Suwazono et al. (2006) paper is another example, which identifies urinary cadmium concentrations, which are lower than the critical concentrations previously reported. Thus it adds further support to the application of the 10-fold intraspecies uncertainty factor (see later comment/response). MOE agrees that in view of the difficulties of establishing a NOAEL based on epidemiological studies, a BMD approach may be an alternative to circumvent the application of uncertainty factors for estimation of the NOAEL.

Comment: The study by Thun et al. (1991) considered the potential toxicological effects of cadmium with respect to marker compounds in the body, such as creatinine. However, the use of marker compounds such as creatinine in these studies can be problematic, as documented by Barr et al. (2005), so some care is required in interpreting such values, particularly in older individuals that are assumed to be the target population of interest for cadmium exposure.


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Response: The normalization of urinary biomarkers of exposure and effect with urinary creatinine levels are routinely used and applied to spot urine samples to account for urine dilution. This is done as part of acceptable practice that enables conclusions to be drawn within acceptable ranges. As mentioned in the Barr et al., (2005) paper, the WHO recommends exclusionary guidelines for urinary creatinine concentrations to identify individual samples that are invalid for chemical analysis. Therefore we agree that some care is required in the interpretation of studies that use creatinine-adjustments.

Comment: The MOE Rationale Document (and the EC 2001 Position Paper) relies heavily on the meta-analysis conducted by Thun et al. (1991) who estimated that 100 ug/m3 – years was the LOAEL (lowest adverse effect level) for workers occupationally exposed to Cd. In Thun’s meta-analysis, only three cases of proteinuria were identified from seven studies at exposures of 100 ug/m3 – years. The incidence rate of 2.4% at an exposure of 100 ug/m3 – years was identical to the background incidence of proteinuria. Therefore, it would appear that the 100 ug/m3 – years selected as a LOAEL by Thun et al. (1991) would be more correctly interpreted as a NOAEL (a no adverse effect level). Therefore, the 5-fold safety factor for LOAEL-NOAEL extrapolation is unwarranted. Given that the proteinuria at 100 ug/m3 – years is not different from the background incidence, the further application of a 10-times factor to account for “inter individual variability” is likely to result in an overly conservative result, and its use is questionable. The resulting lifetime ambient air concentration at this level is 292 ng/m3 (derived using the formula on p. 29 of the Rationale Document, except with Ontario assumptions of 240 working days per year rather than 225 used in the European Union). Since no safety factor application is justifiable, the AAQC would be more appropriately set at 300 ng/m3.

Response: MOE has re-assessed the 2.5% background prevalence rate referred to in the Thun et al. (1991) study, the deliberations of the EC expert working group(European Commission, 2000) regarding extrapolation from a LOAEL to a NOAEL and other recent findings of background prevalence of tubular proteinuria in the general population. Several factors became apparent:

- There appears to be variability in background prevalence (or what has been accepted as background prevalence in studies) with values between 2.5 to 10% being cited.

- These values are dependent on age and also on other factors, which may not have been sufficiently excluded from the studies which identified background prevalence.

- From the pooled studies, Thun et al. (1991) identifies a gradual rise in the prevalence of kidney dysfunction from 2.4 % to 8.8% at cumulative exposures between 100 and 499 µg/m3 – years. The prevalence identified (i.e., 2.4%) with the low end of the cumulative exposures of 100 µg/m3 – years in the Thun et al.


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(1991) study, is below the low end of the background prevalence range of 2.5 - 10%. Hence selecting the 100 µg/m3 – years as the point of departure for standard development was considered appropriate.

Based on these factors (more detail in revised section 7 of Decision Document), MOE concluded that the 100 µg/m3 – years can be interpreted as a likely NOAEL and hence the uncertainty factor of 5 for extrapolating from a LOAEL to a NOAEL is not required.

Regarding the intraspecies uncertainty factor of 10, MOE and most regulatory agencies, consider this factor as necessary since this is to provide protection for those individuals who may be particularly sensitive to the substance in question. The EC expert group notes that women may be at higher risk than men because iron deficiency increases intestinal cadmium absorption, that in large population groups, early sign of renal effects are detected at cadmium-in-urine levels of 0.5-2 µg/g creatinine, that diabetic patients may be more susceptible to the renal effects of cadmium, and that increased urinary cadmium levels may be also associated with increased risk of bone fractures in women and height loss in men at relatively low levels of exposure, which may have important health implications for the elderly. In addition children could be a potentially sensitive sub-population, who are not being assessed and the intraspecies uncertainty factor would address this uncertainty and provide extra protection.

Furthermore, recent studies (Akesson, A. et al.; 2002; Akesson, A. et al.; 2005; Noonan, C. W. et al.; 2002; Suwazono, Y. et al.; 2006) appear to identify sensitive sub-populations and point to the fact that tubular renal effects occurred at lower cadmium levels than previously demonstrated.

For these reasons, an intraspecies uncertainty factor of less than 10 does not seem to be justified.

Comment: Acknowledgement and support was expressed by stakeholders for the significant lowering of the air standard, but consideration of Cd as a carcinogen was also encouraged. The consideration of Cd as a carcinogen in the derivation of the standard is supported by IARC (1993), the 11th Report on Carcinogens (National Toxicology Program - NTP, 2005), and California EPA . The consideration of Cd as a carcinogen is also supported by a weight of evidence of multiple species of animals, in vivo and in vitro models (NTP, 2005). It was acknowledged that, as outlined by WHO and EC, experts indicated that findings from available occupational epidemiological studies are inconclusive due to concurrent arsenic and cadmium exposure. Moreover, the genotoxic studies on cadmium are inconclusive. However stakeholders expressed agreement with the NTP (2005) assessment, that it is unlikely that the increased risk of lung cancer found in occupational studies was due entirely to confounding factors. In addition, animal studies have demonstrated increased incidence of lung tumours from


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exposure to Cd. Stakeholders recommended that since US EPA, CalEPA and Health Canada all developed carcinogenic reference values or unit risks, the MOE should recalculate the proposed standard based on cadmium’s carcinogenicity.

Response: It is important to make note of some key factors that were behind MOE’s previous proposal for the cadmium standard:

• MOE agrees with leading world health agencies (e.g. WHO, EC, IARC, ATSDR and Health Canada) that qualitatively cadmium is likely to be carcinogenic.

• MOE also agrees with the WHO and the EC that, because of the identified and controversial influence of concomitant exposure to arsenic in the key epidemiological studies used, quantitative derivations of a carcinogenicity-based standard (i.e., unit risk) are not reliable. The EC Position Paper noted: “It must be remembered that WHO (1997) has refrained from recommending a quantitative cancer risk estimate because of the uncertainties concerning qualitative and quantitative aspects of possible carcinogenicity of cadmium” (European Commission, 2000)

• The carcinogenicity of cadmium was discussed and acknowledged in the Rationale Document. In addition MOE agrees with the NTP Report on Carcinogens, Eleventh Edition that ‘although other factors that could increase the risk of cancer, such as co-exposure to arsenic, were present in several of the epidemiological studies, it is unlikely that the increased risk of lung cancer was due entirely to confounding factors.

• In considering the European Commission’s approach to be the most appropriate for deriving Ambient Air Quality Criteria, the MOE implicitly agreed with the fact that an annual mean concentration level of 5 ng/m3 as derived (by the EC) from non-cancer effects, provides also an appropriate level of protection from cancer risk due to exposure to cadmium.

MOE, based on other comments received, is addressing another aspect of the EC derived guideline (i.e., the original point of departure being considered a LOAEL or a NOAEL; see previous comment). This and other factors necessitated reconsideration of the final derivation of the standard. These factors are:

• Changing the point of departure to a NOAEL would result in a standard that would no longer retain the appropriate level of protection from cancer risk that was intended by the expert group developing the EC guideline.

• In response to stakeholder comments, MOE feels that it should provide a closer linkage to a carcinogenicity basis when deriving the cadmium standard, while at the same time acknowledge the uncertainty in this area.

• The EC expert group notes that: Cadmium has been tested in genotoxicity assays with mixed results.


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A plausible explanation would be that several mechanisms are contributing to the overall effect, suggesting linear as well as nonlinear partial components. In this case, linear extrapolation is likely to overestimate the “real” effect, and some kind of sublinearity should result as an overall exposure-effect relationship. A threshold might be possible, too, but at present evidence is not strong enough to suggest adoption of a threshold hypothesis.

Therefore, to address the above considerations, including uncertainty and to reasonably provide additional protection for human health, a modifying uncertainty factor of 5 was applied to address the possible carcinogenicity in the derivation of the standard.

Comment: Standard was proposed based on the perception that over-all Cadmium emissions were increasing. In fact, the increase in NPRI reporting of cadmium emissions over the 6 years from 1999 to 2004 is mostly attributable to changes in reporting requirements.

Response: In fact, as part of the 2004 NPRI (National Pollution Release Inventory) data for the years 1999-2004, the available data indicate that due to the lowering of the reporting threshold from 10 tonnes to 50 kg, there is a great increase in the number of facilities reporting cadmium emissions and hence in the spatial distribution of emissions, as well as, an increase in the reported total emissions of cadmium in the province of Ontario

In addition to emission quantities, the prioritization of cadmium for review of standards is based on additional factors such as the toxicology and possible impacts on health, and the guideline update status of Ontario, as well as, other jurisdictions.

Comment: If ½-hour and 24-hour standards are to be set, to be scientifically valid they must be based on acute studies and not on pre-defined conversion factors.

Response: The Ministry’s 24-hour standards and Ambient Air Quality Criteria (AAQCs), with 24-hour averaging times, are intended to protect against chronic exposures and are not intended to be interpreted as an acute effect-based standard. In this case, the epidemiological study of Thun et.al. (1991) is used to derive a standard, that is protective against chronic exposures, starting from adverse effects observed in a chronic exposure period over an average occupational working lifetime, converted to continuous lifetime exposure in the average population, followed by application of appropriate uncertainty factors.


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In this particular case, since the standard is partially based on carcinogenicity, and partially on kidney effects, an annual value is derived as the primary AAQC which is converted using conversion factors to both 24-hour and ½-hour standards. The ½ hour standards are needed because of modelling needs until the new models are fully phased in. These historical conversion factors are based on both meteorological considerations, as well as, reasonably conservative empirical relationships of ambient air concentrations of a common pollutant between short-term and long-term measurements. Their purpose therefore is to ensure that if the short-term limit (e.g., ½ hour) is met, then air quality standards based on longer term exposure (e.g., 24-hour or annual) will not be exceeded. As a result, the Ministry interprets the 24-hour standards and AAQCs as daily exposure concentrations to humans (including sensitive subgroups) that is likely to be without an appreciable risk of adverse effects during a lifetime.

Comment: An air standard for metals should be based on the PM10 fraction of airborne particulate matter. This fraction represents the inhalable component of airborne particulate matter, and therefore should provide the basis for an air standard. The exception would be if a multimedia assessment indicates that the larger particulate components (>PM10) are important components of exposure. In such cases, the standard based on TSP could be relevant. However, such a TSP-based standard would necessarily be based on a proper multi-media assessment.

Response: Although the particle size below 10 µm (PM10) is relevant for inhalation exposure, larger particles in total suspended particulates (TSP) are also relevant to other exposure pathways from which airborne cadmium can contribute to the body burden. This is of particular relevance for persistent contaminants like cadmium that can build up in the local environment from emitting facilities. Furthermore, there are additional factors taken into consideration:

The burden of cadmium to the kidney causing effect can occur irrespective of the route of exposure (systemic toxicant).

Several studies indicate that people living near point sources of airborne

cadmium have higher exposures to cadmium than those living farther away from both operating (Jarup, L. et al.; 1995) and closed facilities, including contribution to backyard vegetables (Hellstrom, L. et al.; 2007).

The WHO (2000) air guideline recommends an air standard of 5 ng/m3 to

minimize cadmium deposition to agricultural soils, thus limiting an increase in exposure including future dietary intake.


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An evaluation near copper, zinc, and nickel, smelters and refineries in Canada (Environment Canada, 2000) reported that Canadian cadmium deposition rates fall in the range observed in Europe. Therefore, caution similar to the WHO and the EC regarding deposition to agricultural soils should be exercised.

For these reasons the cadmium air standard is intended to account for cadmium in total suspended particulates and not just in the PM10 fraction alone.

General Comments:

In addition to technical comments on this specific substance, MOE received ‘general’ comments related to the standard setting process, implementation of standards and odour issues. Some of these comments formed part of the response to the Rationale Documents, which were posted from June 26, 2006 to September 25, 2006. Other comments were in response to the "Proposal to amend Ontario Regulation 419/05: Air Pollution-Local Air Quality" posted from June 15 to September 25, 2006, with a subsequent posting April 7, 2007 to May 7, 2007 of the proposed draft amendments to O. Reg. 419/05. With the June to September, 2006 posting the MOE also introduced a “Proposed Approach for the Implementation of Odour-Based Standards and Guidelines” to which it also received comments.

A detailed summary of these general comments and MOE’s responses to them can be found in the following two related postings:

1) EBR #: 010-0000 – Proposal to Amend Ontario Regulation 419/05: Air Pollution-Local Air Quality under the Environmental Protection Act; and

2) EBR #: RA06E0006 – Proposed Approach for the Implementation of Odour-Based Standards and Guidelines.

http://www.ebr.gov.on.ca/ERS-WEB-External/displaynoticecontent.do?noticeId=MTAwMDAw&statusId=MTQ5Mzgx&language=en

http://www.ebr.gov.on.ca/ERS-WEB-External/displaynoticecontent.do?noticeId=MTAwMDAw&statusId=MTQ5Mzgx&language=en

http://www.ebr.gov.on.ca/ERS-WEB-External/displaynoticecontent.do?noticeId=Mjc4ODc=&statusId=Mjc4ODc=&language=en

http://www.ebr.gov.on.ca/ERS-WEB-External/displaynoticecontent.do?noticeId=Mjc4ODc=&statusId=Mjc4ODc=&language=en


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7.0 Considerations in the Development of an Ambient Air Quality Criterion for Cadmium

The current Ontario 24-hour Ambient Air Quality Criterion (AAQC) for cadmium is 2 μg/m3. The half-hour point of impingement (POI) standard is 5 μg/m3. The basis for both of the standards, set in 1974, was protection of human health.

Inhalation of cadmium has been shown to result in lung cancer in some epidemiological studies, which were not without confounding factors. A number of assessments of human health studies carried out by different agencies have recommended reducing the cadmium emissions from man-made sources. New studies in the literature have provided some evidence that cadmium affects the DNA repair system in a number of species in different environments.

It is clear that the present standards for the AAQC and 0.5-hr POI of 2 µg/m3 and 5 µg/m3 cadmium, respectively, are not sufficiently protective of human health and require reassessment. However, it should be noted that the measured concentrations of cadmium in inhalable particles are significantly lower than the standards.

In terms of one of the concerns noted above, the research, mechanism, and the interpretation of the effects of cadmium (and other metals) on the DNA repair systems is at an early stage. Agencies have not reached consensus as to how to incorporate such information into the standard setting process, other than to point towards reduction of cadmium and other metal emissions.

The second concern noted above has to do with the evidence of lung cancer from cadmium exposure and the most appropriate methodology to use to guide the standards setting approach.

The US EPA and the California EPA, in 1991 and 1994 respectively, both used the unit risk approach, based on the Thun at al., (1985) epidemiological study to develop cancer-based guidelines.

In particular, the US EPA has published an inhalation unit risk based on an occupational exposure study of male workers by Thun et al., (1985). This study suggested that there was 2-fold excess risk of lung cancer for a cohort of cadmium smelter workers. The minimum employment period was six months and the cohort was followed for a period ranging from 9 to 38 years. The finding of the study indicated that inhalation exposure to cadmium led to lung and tracheal tumors. The data from this study was used to generate an inhalation unit risk of 1.8 x 10-3 (µg/m3)-1. This extrapolates to a 1-in-a-million risk level of 0.6 ng/m3.


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Neither the US EPA nor the California EPA has updated their guidelines for over 10 years.

More recent developments, by other agencies, concerning this study, Thun et al., (1985), and other evidence that has bearing on selecting the most appropriate approach in developing air quality standards for Ontario, are as follows:

• A review of cadmium by the ATSDR (1999) concluded that the analysis presented in the Thun et al., (1985) study did not account for the confounding factors of smoking and concomitant exposure to arsenic dusts. It was noted that the Thun et al., (1985) study was based on a cohort from a cadmium recovery plant. A study using workers from a cadmium alloy manufacturing plant in England found that cadmium oxide fumes increased the risk of chronic non-malignant diseases of the respiratory tract but, did not find that the data supported lung cancer associated mortality (Sorahan, T. et al.; 1995). A subsequent reanalysis using cumulative exposure estimates adjusted for detailed job histories indicated that lung cancer mortality was not associated with cadmium exposure alone (Sorahan, T. and Lancashire, R. J., 1997). It was found that the concomitant exposure to arsenic trioxide was likely responsible for cadmium-associated mortality.

• The World Health Organization also noted (World Health Organization, 2000) that because of the identified and controversial influence of concomitant exposure to arsenic in the epidemiological study of Thun et. al., (1985), no reliable unit risk can be derived to estimate the excess lifetime risk for lung cancer. They note further that there is evidence from recent studies (Sorahan, T. and Lancashire, R. J., 1997), that the unit risk of 1.8 x 10-3 (µg/m3)-1, based on the Thun et al., (1985) study as derived by the US EPA, might be substantially overestimated owing to confounding by concomitant exposure to arsenic. The WHO, derived their annual guideline value based on renal effects observed in populations where higher cadmium loadings were found.

• The US EPA themselves noted (see Section 10.1, this document), in discussing the Thun et. al., (1985) study, that because there was a lack of clear-cut evidence of a causal relationship attributable to the cadmium exposure only, this study is considered to supply limited evidence of human carcinogenicity.

• The European Commission (European Commission, 2000), in a Position Paper by a multi-national expert group, considered the following in developing a guideline for cadmium:

▪ They considered both the animal and the occupationally-based human studies with respect to cadmium-in-air exposure.


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▪ The EC considers the non-carcinogenic effects on the kidney to be the critical indicators of inhalation exposure to cadmium.

▪ Although the EC assessment considered both the carcinogenic and non-carcinogenic effects, it was determined that the weight-of-evidence did not indicate that carcinogenicity was linked to cadmium exposures alone. The prime observation that led to this conclusion was that the results of cadmium-induced genotoxicity were inconclusive; this would invalidate a reliable linear extrapolation to a low level exposure, typically expected, by providing an overestimate of the risk.

▪ In developing the guideline, the key occupational studies considered were those of Thun et al., (1991) and Lauwerys et al., (1974). In the Thun study, a range of 100 to 499 µg/m3-years of cumulative exposure was calculated as the level at which kidney effects could be expected in most workers. Sensitive individuals could develop adverse effects at even lower levels. The lower end of the proposed range was used to derive a LOAEL. Applying conversion factors of an 8-hour work day for 225 days per year over a 75 year lifetime average, a LOAEL of 270 ng/m3 of continuous exposure was derived. Applying an uncertainty factor of 5 for LOAEL to NOAEL extrapolation and 10 for intraspecies variability, a chronic exposure of 5 ng/m3 (annual mean) was calculated to provide reasonable protection.

▪ In summary, the consensus of the group was that an annual mean concentration level of 5 ng/m3 as derived from non-cancer effects provides also an appropriate level of protection from cancer risk due to exposure to cadmium.

While the non-cancer-based cadmium standard derived by the European Commission is based on conservative assumptions of occupational exposures, it is an order of magnitude higher when compared to the value derived using the cancer slope factor and applying a risk criterion of 1 in a million.

In addition to the direct effect of inhalation exposure on human health, the EC also considered exposure through indirect means such as the deposition of cadmium-containing dusts on soil and plants, the transfer of cadmium to the food chain via deposition on agricultural crops, and, via dermal contact and ingestion of soil. Therefore, the air quality guideline is also intended to minimize these indirect impacts of airborne cadmium. Applying an uncertainty factor of 5 for LOAEL to NOAEL extrapolation and 10 for intraspecies variability, a chronic exposure of 5 ng/m3 (annual mean) was calculated to be the recommended guideline value.


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The stakeholders, who commented on the Information Draft, raised concerns over the use of cancer-based criteria on which to set an air standard in Ontario. They suggested that the data for the non-cancer endpoint of kidney damage was the most appropriate basis from which an ambient air quality criteria could be derived. Scientific criteria documents, published by other agencies (i.e., World Health Organization, European Union, and ATSDR) were cited for consideration.

Based on the above evidence, recent reanalysis of studies by several agencies and stakeholder comments, the Ministry in its previous Rationale Document proposal (MOE, 2006) considered the European Commission’s approach to be the most appropriate for deriving Ambient Air Quality Criteria.

In response to the Rationale Document, stakeholders provided comments (for more detail see comments/responses) in the following 3 important areas pertaining to MOE’s previous proposal:

1. The 100 µg/m3-years in the meta-analysis by Thun et al. (1991) would more appropriately be interpreted as a NOAEL instead of a LOAEL, since the incidence rate of 2.4 % identified at this level is identical to the background incidence of proteinuria. Therefore, the 5-fold safety factor for LOAEL-NOAEL extrapolation is unwarranted.

2. In addition, given that the proteinuria at 100 ug/m3-years is not different from the background incidence, the further application of a 10-times factor to account for “inter individual variability” is likely to result in an overly conservative result, and its use is questionable.

3. Consideration of cadmium as a carcinogen was encouraged while it was acknowledged that, as outlined by WHO and EC, experts indicated that findings from available occupational epidemiological studies are inconclusive due to concurrent arsenic and cadmium exposures. Some recommendations suggested that since US EPA, CalEPA and Health Canada all developed carcinogenic reference values or unit risks, the MOE should recalculate the proposed standard based on cadmium’s carcinogenicity.

MOE has considered these comments sequentially as detailed below and re-assessed the associated information, which necessitated reconsideration of the final derivation of the standard.


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1. After re-assessing the 2.5% background prevalence rate referred to in the Thun et al. (1991) study, the deliberations of the EC expert working group (European Commission, 2000) regarding extrapolation from a LOAEL to a NOAEL and other recent findings of background prevalence of tubular proteinuria in the general population, several factors became apparent:

• There appears to be variability in background prevalence (or what has been accepted as background prevalence in studies) with values between 2.5 to 10% being cited (European Commission, 2000; Suwazono, Y. et al.; 2006; Thun, M. J. et al.; 1991).

• As the prevalence of proteinuria in the general population is also associated with other detriments affecting the kidney, such as diabetes or underlining kidney disease it is not clear whether the epidemiological studies relied upon by Thun et al., (1991) have sufficiently excluded individuals from their analysis or have controlled for confounders sufficiently.

• From the pooled studies, Thun et al. (1991) identifies a gradual rise in the prevalence of kidney dysfunction from 2.4 % to 8.8% at cumulative exposures between 100 and 499 µg/m3-years. The prevalence identified (i.e., 2.4%) with the low end of the cumulative exposures of 100 µg/m3-years in the Thun et al. (1991) study, is below the low end of the background prevalence range of 2.5 - 10%. Hence selecting the 100 µg/m3 -years as the point of departure for standard development was considered appropriate.

Based on these factors, it was concluded that the 100 µg/m3-years can be interpreted as a likely NOAEL and hence the uncertainty factor of 5 for extrapolating from a LOAEL to a NOAEL is not required.

2. Regarding the intraspecies uncertainty factor of 10, MOE and most regulatory agencies, consider this factor as necessary since this is to provide protection for those individuals who may be particularly sensitive to the substance in question. The EC expert group(European Commission, 2000) notes that women may be at higher risk than men because iron deficiency increases intestinal cadmium absorption, that in large population groups, early sign of renal effects are detected at cadmium-in-urine levels of 0.5-2 µg/g creatinine, that diabetic patients may be more susceptible to the renal effects of cadmium, and that increased urinary cadmium levels may be also associated with increased risk of bone fractures in women and height loss in men at relatively low levels of exposure, which may have important health implications for the elderly. In addition children could be a potentially sensitive sub-population, who are not being assessed and the intraspecies uncertainty factor would address this uncertainty and provide extra protection.


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Furthermore, recent studies (Akesson, A. et al.; 2002; Akesson, A. et al.; 2005; Noonan, C. W. et al.; 2002; Suwazono, Y. et al.; 2006) appear to identify sensitive sub-populations and point to the fact that tubular renal effects occurred at lower cadmium levels than previously demonstrated.

For these reasons, an intraspecies uncertainty factor of less than 10 does not seem to be justified.

3. Regarding the linkage of the cadmium standard to a carcinogenicity basis several points need to be noted or reiterated.

It is important first to reiterate some key factors that were behind MOE’s previous proposal for the cadmium standard:

• MOE agrees with leading world health agencies (e.g. WHO, EC, IARC, ATSDR and Health Canada) that qualitatively cadmium is likely to be carcinogenic.

• MOE also agrees with the WHO and the EC that, because of the identified and controversial influence of concomitant exposure to arsenic in the key epidemiological studies used, quantitative derivations of a carcinogenicity-based standard (i.e., unit risk) are not reliable. The EC Position Paper noted: “It must be remembered that WHO (1997) has refrained from recommending a quantitative cancer risk estimate because of the uncertainties concerning qualitative and quantitative aspects of possible carcinogenicity of cadmium” (European Commission, 2000)

• The carcinogenicity of cadmium was discussed and acknowledged in the Rationale Document and this is retained in the current Decision Document. In addition MOE agrees with the NTP Report on Carcinogens, Eleventh Edition that ‘although other factors that could increase the risk of cancer, such as co-exposure to arsenic, were present in several of the epidemiological studies, it is unlikely that the increased risk of lung cancer was due entirely to confounding factors.

• In considering the European Commission’s approach to be the most appropriate for deriving Ambient Air Quality Criteria, the MOE implicitly agreed with the fact that an annual mean concentration level of 5 ng/m3 as derived (by the EC) from non-cancer effects, provides also an appropriate level of protection from cancer risk due to exposure to cadmium.

MOE, based on other comments received, has addressed another aspect of the EC derived guideline (i.e., the original point of departure being considered a LOAEL or a NOAEL; issue # 1 above). This and other factors necessitated reconsideration of the final derivation of the standard. These factors are:


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• Changing the point of departure to a NOAEL would result in a standard that would no longer retain the appropriate level of protection from cancer risk that was intended by the expert group developing the EC guideline.

• In response to stakeholder comments, MOE feels that it should provide a closer linkage to a carcinogenicity basis when deriving the cadmium standard, while at the same time acknowledge the uncertainty in this area.

• The EC expert group (European Commission, 2000) notes that: ▪ Cadmium has been tested in genotoxicity assays with mixed results. ▪ A plausible explanation would be that several mechanisms are

contributing to the overall effect, suggesting linear as well as nonlinear partial components. In this case, linear extrapolation is likely to overestimate the “real” effect, and some kind of sublinearity should result as an overall exposure-effect relationship. A threshold might be possible, too, but at present evidence is not strong enough to suggest adoption of a threshold hypothesis.

Therefore, to address the above considerations, including uncertainty and to reasonably provide additional protection for human health, application of a modifying uncertainty factor of 5 to address the possible carcinogenicity in the derivation of the standard is necessitated.

In addition to the three issues discussed above, it was felt that the relevance of particle size with respect to the cadmium standard deserved some further assessment, clarification and/or reiteration.

Although the particle size below 10 µm (PM10) is relevant for inhalation exposure, larger particles in total suspended particulates (TSP) are also relevant to other exposure pathways from which airborne cadmium can contribute to the body burden. This is of particular relevance for persistent contaminants like cadmium that can build up in the local environment from emitting facilities. Furthermore, there are additional factors that need to be considered:

The burden of cadmium to the kidney causing effect can occur irrespective of the route of exposure (systemic toxicant).

Several studies indicate that people living near point sources of airborne cadmium have higher exposures to cadmium than those living farther away from both operating (Jarup, L. et al.; 1995) and closed facilities, including contribution to backyard vegetables (Hellstrom, L. et al.; 2007).

The WHO (2000) air guideline recommends an air standard of 5 ng/m3 to minimize cadmium deposition to agricultural soils, thus limiting an increase in exposure including future dietary intake.

The rationale behind the guideline value proposed by the European Commission, considered the toxicological endpoint (kidney effects) and also recognized the


44

importance of deposition of cadmium in areas with higher pre-existing levels of cadmium. The recommended air quality guideline, was expected to be protective of health impacts via inhalation and also minimize impacts due to deposition.

An evaluation near copper, zinc, and nickel, smelters and refineries in Canada (Environment Canada, 2000) reported that Canadian cadmium deposition rates fall in the range observed in Europe (European Commission, 2000). Therefore, caution similar to the WHO and the EC regarding deposition to agricultural soils should be exercised.

For these reasons the cadmium air standard is intended to account for cadmium in total suspended particulates and not just in the PM10 fraction alone.

In summary, based on the above re-assessment, the rationale of the EC expert group has been modified. The continuous lifetime exposure of 270 ng/m3 for the general population is still derived from the cumulative occupational exposure of 100 µg/m3-years (this being below the range of background prevalence) as was done by the EC from the Thun et al., (1991) study, except that this is now considered a likely NOAEL for continuous lifetime exposure. Applying an uncertainty factor of 10 for intraspecies variability and a modifying uncertainty factor of 5 to address carcinogenicity (i.e., uncertainty and additional protection of human health), a chronic exposure of 5 ng/m3 (annual average) of cadmium in total suspended particulates was calculated.

8.0 Decision

The Ministry of the Environment has reviewed and considered air quality guidelines and standards as well as the derivation approaches used by leading agencies worldwide as well as advice from Ontario stakeholders. Based on recent evidence and recent reanalysis of studies by the Agency for Toxic Substances and Disease Registry (ATSDR), the World Health Organization (WHO), the European Commission (EC) and stakeholder comments, the Ministry considers the EC’s approach, modified by input from comments received, to be the most appropriate for developing air quality standards. In particular, the non-cancer endpoint of kidney damage, together with the provision of additional protection of human health with respect to carcinogenicity, were considered to provide the most appropriate guideline value on the basis of the studies and plausibility of the mechanisms. Accordingly, the annual cadmium ambient air quality criterion for Ontario is proposed to be 5 ng/m3 of cadmium in total suspended particulates.

The Ministry of the Environment typically uses a factor of 5 to convert from guidelines based on annual average concentrations to 24-hour average concentrations and a factor of 3 to convert from guidelines based on 24-hour average concentrations to half-hour point-of-impingement limits. These factors are derived from empirical


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measurements and are selected to ensure that if the short-term limit is met, air quality guidelines based on longer-term exposures will not be exceeded.

After an evaluation of the scientific rationale of air guidelines from leading agencies, an examination of current toxicological research, and comments from stakeholders, the following standards are set for cadmium and cadmium compounds:

• An annual Ambient Air Quality Criterion (AAQC) of 5 ng/m3 (nanograms per cubic metre of air) for cadmium and cadmium compounds based on kidney effects and carcinogenicity associated with exposure to these compounds ; and

• A 24-hour average AAQC of 25 ng/m3 (nanograms per cubic metre of air) for cadmium and cadmium compounds based on kidney effects and carcinogenicity associated with exposure to these compounds ; and

• A half-hour standard of 75 ng/m3 (nanograms per cubic metre of air) for cadmium and cadmium compounds based on the kidney effects and carcinogenicity associated with exposure to these compounds

These effects-based AAQCs and the corresponding effects-based half hour standards will be incorporated as standards into Ontario Regulation 419/05: Air Pollution – Local Air Quality (O. Reg. 419/05). The AAQCs (except the annual AAQC) will be incorporated into Schedule 3 of O. Reg. 419/05; the half-hour standard will be incorporated into Schedule 2.

MOE generally proposes a phase-in period for new standards or standards that will be more stringent than the current standard or guideline. The phase-in for this compound is as set out in O. Reg. 419/05.

Among other things, O. Reg. 419/05 sets out the applicability of standards and appropriate averaging times, phase-in periods, types of air dispersion models and when various sectors are to use these models. There are 3 guidelines that support O. Reg. 419/05. These guidelines are:

• “Guideline for the Implementation of Air Standards in Ontario” (GIASO);

• “Air Dispersion Modelling Guideline for Ontario” (ADMGO); and

• “Procedure for Preparing an Emission Summary and Dispersion Modelling Report” (ESDM Procedure).

GIASO outlines a risk-based decision making process to set site specific alternative air standards to deal with implementation barriers (time, technology and economics)


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associated with the introduction of new/updated/ air standards and new models. The alternative standard setting process is set out in section 32 of O. Reg. 419/05.

For further information on these guidelines and O. Reg. 419/05, please see the Ministry’s website http://www.ontario.ca/environment and follow the links to local air quality.

http://www.ontario.ca/environment


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Jamall, I. S., Naik, M., Sprowls, J. J., and Trombetta, L. D. 1989. A comparison of the effects of dietary cadmium on heart and kidney antioxidant enzymes: evidence for the greater vulnerability of the heart to cadmium toxicity. J.Appl.Toxicol. 9 (5): 339-345. URL: PM:2592733. Cited In: ATSDR, 1999.

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Kawamura, J., Yoshida, O., Nishino, K., and Itokawa, Y. 1978. Disturbances in kidney functions and calcium and phosphate metabolism in cadmium-poisoned rats. Nephron 20 (2): 101-110. URL: PM:202886.

Kjellstrom, T and Nordberg, G. F. 1985. Kinetic model of cadmium metabolism. Vol. I. Exposure, dose and metabolism. In: Fridberg, L., Elinder, C. G., and Kjellestrom, T., eds. Cadmium and health: A toxicological and epidemiological appraisal. Boca Raton, FL: CRC Press 179-197.

Koeppe, D. E. 1977. The uptake, distribution, and effect of cadmium and lead in plants. Sci.Total Environ. 7: 197-206.


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Kostial, K., Kello, D., Jugo, S., Rabar, I., and Maljkovic, T. 1978. Influence of age on metal metabolism and toxicity. Environ.Health Perspect. 25: 81-86. URL: PM:720306. Cited In: ATSDR, 1999.

Kostial, K., Blanusa, M., Maljkovic, T., Kello, D., Rabar, I., and Stara, J. F. 1989. Effect of a metal mixture in diet on the toxicokinetics and toxicity of cadmium, mercury and manganese in rats. Toxicol.Ind.Health 5 (5): 685-698. URL: PM:2815101.

Kotsonis, F. N. and Klaassen, C. D. 1978. The relationship of metallothionein to the toxicity of cadmium after prolonged oral administration to rats. Toxicol.Appl.Pharmacol. 46 (1): 39-54. URL: PM:725949. Cited In: ATSDR, 1999.

Kozdroj, J. 2001. Microbial reaction to soil contamination with Cd(II) at different temperatures. Microbiol.Res. 155 (4): 285-290. URL: PM:11297359.

Kozlowska, K, Brzozowska, A, Sulkowska, J, and Roszkowski, W. 1993. The effect of cadmium on iron metabolism in rats. Nutr.res 13 (10): 1163-1172. Cited In: ATSDR, 1999.

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Roane, T. M. and Pepper, I. L. 1999. Microbial Responses to Environmentally Toxic Cadmium. Microb.Ecol. 38 (4): 358-364. URL: PM:10758182.

Roels, H., Bernard, A. M., Cardenas, A., Buchet, J. P., Lauwerys, R. R., Hotter, G., Ramis, I., Mutti, A., Franchini, I., Bundschuh, I., and . 1993. Markers of early renal changes induced by industrial pollutants. III. Application to workers exposed to cadmium. Br.J Ind.Med. 50 (1): 37-48. URL: PM:8431389.

Roels, H. A., Lauwerys, R. R., Buchet, J. P., Bernard, A. M., Vos, A., and Oversteyns, M. 1989. Health significance of cadmium induced renal dysfunction: a five year follow up. Br.J Ind.Med. 46 (11): 755-764. URL: PM:2686749.

Roels, H. A., Lauwerys, R. R., Bernard, A. M., Buchet, J. P., Vos, A., and Oversteyns, M. 1991. Assessment of the filtration reserve capacity of the kidney in workers exposed to cadmium. Br.J Ind.Med. 48 (6): 365-374. URL: PM:2064974.

Rusch, G. M., O'Grodnick, J. S., and Rinehart, W. E. 1986. Acute inhalation study in the rat of comparative uptake, distribution and excretion for different cadmium containing materials. Am Ind.Hyg.Assoc.J 47 (12): 754-763. URL: PM:3799475.

Salpietro, C. D., Gangemi, S., Minciullo, P. L., Briuglia, S., Merlino, M. V., Stelitano, A., Cristani, M., Trombetta, D., and Saija, A. 2002. Cadmium concentration in maternal and cord blood and infant birth weight: a study on healthy non-smoking women. J.Perinat.Med. 30 (5): 395-399. URL: PM:12442603.

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Takenaka, S., Oldiges, H., Konig, H., Hochrainer, D., and Oberdorster, G. 1983. Carcinogenicity of cadmium chloride aerosols in Wistar rats. J Natl.Cancer Inst. 70 (2): 367-373. URL: PM:6571943. Cited In: ATSDR, 1999.

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10.0 Agency-Specific Reviews of Air Quality Guidelines

10.1 Agency-Specific Summary: Federal Government of the United States

1. Name of Chemical:

Cadmium

2. Agency:

U.S. Environmental Protection Agency

3. Guideline Value(s):

No ambient air exposure limits are currently promulgated. As of the current date (February, 1996), there is no Reference Concentration (RfC) for chronic inhalation exposure in the IRIS database (US EPA, 1995). There are, however, quantitative estimates of carcinogenic risk from inhalation exposure. The inhalation unit risk is 1.8×10-3 tumours per µg/m3. Using a two-stage model extrapolation procedure, this represents an additional risk of 1 in 100,000 per 0.006 µg/m3 and 1 in 1,000,000 per 0.0006 µg/m3 of lifetime exposure.

4. Application:

IRIS was developed as a source of consistent risk information on chemicals for use in decision-making and regulatory activities; however, values derived and presented in IRIS, in and of themselves do not represent guidelines or standards. IRIS also contains a summary of current American government regulatory actions under various legislative mandates.

5. Documentation Available:

US EPA, 1995. Integrated Risk Information System (IRIS) Database. U.S. Environmental Protection Agency, Washington, D.C. Newer information does not add to above. However, these groups of compounds are being reassessed (1998).


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Key Reference(s):

Friberg, L., M. Piscator, G.F. Nordberg and T. Kjellstrom, 1974. Cadmium in the Environment, 2nd ed. CRC Press, Cleveland, OH.

Thun, M.J., T.M. Schnorr, A.R. Smith and W.E. Halperin, 1985. Mortality among a cohort of U.S. cadmium production workers: an update. J. Natl. Cancer Inst., 74:325-333.

US EPA (United States Environmental Protection Agency), 1985a. Drinking Water Criteria Document for Cadmium (Final Draft). National Technical Information Service, Washington D.C., as cited in US EPA, 1995.

6. Peer Review Process and Public Consultation:

Peer-reviewed scientific research data, analyses and evaluations from various sources, including a variety of public and government agencies from around the world, and the published scientific literature, were employed in the development of these values. The general assessment methodologies and the chemical-specific information found in IRIS undergo extensive scientific and policy reviews, within the US EPA and within other science-based U.S. regulatory agencies. Much of the information that appears in IRIS is based on documents that have been submitted to scientific peer-review and public review.

7. Status of Guideline:

There is no current US EPA air quality guideline for cadmium in ambient air. Most agencies use the US EPA derived values in basing their guidelines or regulatory standards.

8. Key Risk Assessment Considerations:

The US EPA (IRIS, 1995; US EPA, 1985a), based on the work of Friberg et al. (1974), concludes that a concentration of 200 µg Cd/g wet human renal cortex is the highest renal level not associated with significant proteinuria. The US EPA used a toxicokinetic model to determine the level of chronic human oral exposure (NOAEL) which results in 200 µg Cd/g wet human renal cortex from water and food, but not from air. The US EPA noted that there was controversy surrounding the exact level of cadmium in the cortex that might be considered critical, noting that the values range from 50 μg/g to 300 μg/g. They also point out that measurements from normal humans in the United States and Europe show a range of 25 to 50 μg/g in the kidney cortex (US EPA, 1985a). The US EPA uses this type of risk assessment to set guidelines for cadmium in drinking water and food items (1995).


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It is policy, however, to set guidelines based on carcinogenicity if a substance is judged to be, at least, a probable human carcinogen. The US EPA classifies cadmium as a Group B1: probable human carcinogen, based on the judgment that there is limited evidence from human occupational epidemiological studies of cadmium that is consistent across investigators and study populations, and on the judgment that there is sufficient evidence of carcinogenicity in rats and mice by inhalation and by intramuscular and subcutaneous injection. According to the US EPA, seven studies in rats and mice, wherein cadmium salts (acetate, sulfate, chloride) were administered orally, have shown no evidence of carcinogenic response (US EPA, 1995). Therefore, for air as the route of exposure, the US EPA relies on a risk characterization based on carcinogenicity.

A unit risk of 1.8×10-3 per μg/m3 was calculated using a two-stage model which used data reported in Thun et al. (1985). In this study, according to the US EPA (1995), a 2-fold excess risk of lung cancer was observed in cadmium smelter workers in a cohort that was followed from 1940 to 1978. The authors were able to ascertain that the increased lung cancer risk was probably not due to the presence of arsenic or to smoking (Thun et al., 1985). The US EPA notes, however, that because there was a lack of clear-cut evidence of a causal relationship attributable to the cadmium exposure only, this study is considered to supply limited evidence of human carcinogenicity.

The US EPA (1995) reports that an excess lung cancer risk was also observed in three other studies. These, however, were compromised by the presence of other carcinogens (arsenic, smoking) in the exposure, or by a small population (Varner, 1983; Sorahan and Waterhouse, 1983; Armstrong and Kazantis, 1983, all as cited in US EPA, 1995). Studies of workers exposed to cadmium dust or fumes provided evidence of a positive association with prostate cancer, but these were considered inadequate because of the small number of cases in each study.

Exposure of Wistar rats by inhalation to cadmium as cadmium chloride at concentrations of 12.5, 25 and 50 μg/m3 for 18 months, with an additional 13-month observation period, resulted in significant increases in lung tumours (Takenaka et al., 1983). An inhalation unit risk for cadmium based on this study is 9.2×10-2 per μg/m3. While this estimate is higher than that derived from human data (1.8×10-3 per μg/m3), and is thus more conservative, it was felt that the use of available human data was more reliable because of species variations in response and the type of exposure (cadmium salt versus cadmium fume and cadmium oxide) (US EPA, 1995). The present value on the IRIS database has been derived from the human epidemiological data.


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9. Key Risk Management Considerations:

None, since no guideline for ambient air exists. However, cadmium is being listed as a Hazardous Air Pollutant (HAP) under the U.S. Clean Air Act.

10. Multimedia Considerations of Guidelines:

None are reported except that cadmium exposure by the oral route through food and water is not considered to be associated with carcinogenicity.

11. Other Relevant Factors:

According to the US EPA (1995), results of mutagenicity tests in bacteria and yeast have been inconclusive, while positive responses have been obtained in mutation assays in Chinese hamster cells and in mouse lymphoma cells. Cadmium treatment in vivo or in vitro appears to interfere with spindle formation and to result in aneuploidy in germ cells of mice and hamsters. Conflicting results have been obtained in assays of chromosomal aberrations in human lymphocytes treated in vitro or obtained from exposed workers.


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10.2 Agency-Specific Summary: World Health Organization


Cadmium

2. Agency:

World Health Organization


A guideline value of 5 ng/m3 (0.005 μg/m3) has been established. The findings of renal effects in populations living in areas contaminated by past emissions of cadmium indicates that increases of cadmium to the body burden of these populations should be limited by a stringent air standard. In rural areas, present levels of 0.001 to 0.005 μg/m3 should not be allowed to increase. In urban areas without agricultural activities and in industrialized areas, levels of 0.01 to 0.02 μg/m3 may be tolerated. An increase in existing levels should not be permitted. A value of 0.005 μg/m3 is based on the cumulative intake of food-based cadmium as well. Review of recent documents does not recommend any change to this value.

4. Application:

"The guidelines are intended to provide background information and guidance to governments in making risk management decisions, particularly in setting standards. It should be strongly emphasized that the guideline values are not to be regarded as standards in themselves." (WHO, 1987, pg. xiii).


WHO, 1987. Air Quality Guidelines for Europe. WHO Regional Publications, European Series No. 23, World Health Organization, Regional Office for Europe, Copenhagen, Denmark. 426 p. New documents do not suggest different values.

World Health Organization (2000) Air Quality Guidelines for Europe (2nd Edition) Regional Office for Europe, Copenhagen. WHO Regional Publications, European Series, No. 91.

Key Reference(s):


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Friberg, L., M. Piscator, G.F. Nordberg and T. Kjellstrom, 1974. Cadmium in the Environment, 2nd ed. CRC Press, Cleveland, OH.

Kjellstrom, T. and G.F. Nordberg, 1978. A kinetic model of cadmium metabolism in the human being. Environmental Research, 16:248-269.


Scientific background documents were prepared by experts and submitted for discussion to working groups consisting of international experts. After a series of meetings and internal and external reviews by experts and representatives of Member States of the Region, the resultant conclusions and recommendations were presented at a final meeting and adopted by consensus of the representatives. In addition, peer-reviewed scientific research data were employed in the development of these documents.


Current, but a review of a number of WHO air quality guidelines is under way.


According to the WHO (2000), dose-response analysis for inhaled cadmium/cadmium compounds on the basis of epidemiological studies from the general population is not possible. Studies considering occupational exposure can be used to derive an indirect estimate of renal dysfunction or lung cancer. An assessment of occupational exposure studies suggested that an eight hour exposure level for cadmium should be below 5 μg/m3. Converting this value to a continuous lifetime exposure yields a permissible concentration of approximately 300 nanograms per cubic meter.

WHO (2000) (and also in the 1987 document) pointed out that cadmium in ambient air is transferred to soil by both wet and dry deposition and can enter the food chain due to uptake by plants. Such an increase in dietary exposure to cadmium will result in a greater dose. Consequently, airborne cadmium and the precipitation of cadmium onto soils should not be allowed to increase.

This is of significant concern because a number of studies have shown that renal effects have occurred in residents living in areas contaminated by past cadmium emissions. As a result, the cadmium body burden of the general population in some parts of Europe should not be allowed to increase. Extrapolation from occupational studies to continuous lifetime exposures results in an annual value of 0.3 μg/m3. This level (0.3 μg/m3) may cause fallout of 10 to 30 mg of cadmium per m2 per year, which would have a significant impact on cadmium uptake in


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plants. Presently, cadmium levels in most urban or industrial centers in Europe are approximately 1/50th of this value. Thus, a guideline value of 5 nanograms per cubic meter is recommended.


Prevention of unwanted increases in exposure to cadmium should be possible through monitoring both the precipitation of cadmium and cadmium concentrations in foodstuffs. Because cadmium is commonly associated with phosphate deposits, it was recommended that the use of fertilizers with low cadmium content will be of great importance.


Air, drinking water and diet were considered in the evaluation.


The guideline discussion assumes that indoor and outdoor concentrations are similar (WHO, 1987).


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10.3 Agency-Specific Summary: State of California


Cadmium

2. Agency:

State of California (Office of Environmental Health Hazard)


The State of California states that the unit risk of 4.2×10-3 tumours per μg/m3 is to be used for evaluation of cancer risks (CAPCOA, 1993). At risk levels of 10-5 and 10-6 this corresponds to concentrations of cadmium in air of 0.0024 μg/m3 and 0.00024 μg/m3 respectively. Several other carcinogenicity risk estimates have been prepared by California authorities, as noted below, but this value is used for air quality risk assessment. This unit risk value has not been changed as of 2006.

4. Application:

"The intent of the Committee in developing the guideline was to provide risk assessment procedures for use in the Air Toxics 'Hot Spots' Program." (CAPCOA, 1993). This program is based on a California State law: the Air Toxics 'Hot Spots' Information and Assessment Act of 1987 (Health and Safety Code Section 44360 et seq.). The act specifies how local Air Pollution Control Districts determine which facilities in their areas will prepare health risk assessments, how such health risk assessments should be prepared and how the results are to be prioritized. These guidelines were prepared to provide consistent risk assessment methods and report presentation to enable: 1) comparisons between facilities, 2) expeditious reviews of risk assessments by reviewing agencies, and 3) minimal revisions and resubmittals of risk assessments. The various health-based exposure levels developed for and employed in this program should not be employed outside the framework of the program. That is to say, the State of California does not consider them to be general, independent, legally enforceable air quality guidelines or limit values at this time.


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CAPCOA, 1993. CAPCOA Air Toxics "Hot Spots" Program. Revised 1992 Risk Assessment Guidelines. Toxics Committee of the California Air Pollution Control Officers Association.

Key Reference(s):

CDHS (California Department of Health Services), 1986. Technical support document: report to the Air Resources Board on Cadmium, part B: health effects of cadmium. In: Public Hearing to Consider the Adoption of a Regulatory Amendment Identifying Cadmium as a Toxic Air Contaminant. State of California Air Resources Board.

California EPA, 1992. Initial Statement of Reasons 22 California Code of Regulations, Section 12705(b): Specific Regulatory Levels Posing No Significant Risk: Arsenic, Butylated hydroxyanisole, Cadmium, Chromium (hexavelant compounds).Friberg, L., M. Piscator, G.F. Nordberg and T. Kjellstrom, 1974. Cadmium in the Environment, 2nd ed. CRC Press, Cleveland, OH.

Kjellstrom, T. and G.F. Nordberg, 1978. A kinetic model of cadmium metabolism in the human being. Environ. Res., 16:248-269.

Takenaka, S., H. Oldiges, H. Konig, D. Hochrainer and G. Oberdorster, 1983. Carcinogenicity of cadmium chloride aerosols in Wistar rats. J. Natl. Cancer Inst., 70:367-71.



Cancer potency slope factors and acute and chronic reference levels were prepared by the California Office of Environmental Health Hazard Assessment (OEHHA). These, as well as the exposure and health assessments, have undergone public review and comment prior to finalization. Peer-reviewed scientific research data were employed in the development of these values. Under the CAPCOA risk assessment process, each assessment is site-specific, and public notice to all exposed individuals is required when the screening process determines that a significant health risk is associated with emissions from a facility. Public input was obtained in identifying and ranking areas and facilities for risk assessment screening, and, according to the documentation, additional input is expected as the process moves forward.


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Current, but updates are possible, with new California risk assessment guidelines being considered in the California Senate.


According to the California Department of Health Services (CDHS, 1986), Friberg et al. (1974) proposed that the renal cortex concentration of 200 μg/g wet weight tissue is a threshold concentration at which adverse effects on the kidney are observed. Using a pharmacokinetic model, they estimated that the ambient air concentrations of 0.65 to 2.5 μg/m3 will lead to a renal cortex concentration of 200 μg/g wet weight, following lifetime exposure. CDHS (1986) concluded that 200 μg/g is not a threshold, based primarily on work by Kjellstrom (1984), who concluded that this level represents a risk of proteinuria for 10% of the human population. CDHS did conclude, however, that a threshold probably does exist. To determine a level in ambient air at which no adverse effects might be assured, CDHS used the data in Friberg et al. (1974) in their own model. They concluded that an ambient air concentration of 0.001 μg/m3 of cadmium is 650 to 2500 times less than that proposed by Friberg et al. (1974). According to CDHS, exposure to an ambient air concentration of 0.01 μg/m3 may pose a risk if the most conservative assumptions by Friberg et al. (1974) are correct, but if the most likely assumptions by Friberg et al. (1974) are correct, then exposure to an ambient air concentration of 0.01 μg/m3 probably does not pose a risk of renal toxicity.

According to the California EPA (1992), an occupational mortality study of workers exposed for at least six months to cadmium dust in a Colorado cadmium production plant was used to estimate a cancer potency factor for the inhalation of cadmium. Using a relative risk model, the least-square estimate and a 95% upper confidence limit of unit risk were 1.6×10-3 cancers per μg/m3 and 4.1×10-3 cancers per μg/m3 respectively. However, using the data by Thun et al. (1985) on Colorado cadmium production workers, the CDHS (1986) also prepared a linear relative risk model of excess risk due to exposure to cadmium. The model was then applied to the California population. A life table was produced for California males and females separately. Based on background hazard of lung cancer, estimates of the cumulative probability of dying of lung cancer up to the age of 79 were computed. Using the linear relative risk model for deaths due to cancer from cadmium exposure, the hazard of lung cancer deaths was calculated, given a continuous exposure to 0.001 μg/m3. Subtracting the background probability of lung cancer deaths, the least-squares risk and upper 95% confidence limit unit risks of 1.6×10-3 and 12×10-3 cancers per μg/m3 were calculated.


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CDHS (1986) using the computer program, GLOBAL79, which is a multi-stage model, also calculated a unit risk of 1.8x10-1 tumours per μg/m3, based on rat lung tumours reported by Takenaka et al. (1983). Lung tumours were the only neoplasms found to be significantly increased in this study. According to the CDHS, this is the only adequate long-term animal inhalation study and is the most relevant animal study to assess the carcinogenic potential of cadmium as an air pollutant. However, California judged that the human data were a more appropriate basis for their risk estimation factor.


The exposure guidelines were prepared for non-cancer and cancer-based endpoints. The cancer-based value is to be used in a screening risk assessment to determine the maximum off-site cancer risk for exposed human populations. The process is not readily comparable to the air quality guideline approach to non-carcinogens. The non-cancer guidelines are based on the most sensitive adverse health effect reported in the scientific literature and are designed to protect the most sensitive individuals in the population.

There are options for addressing the possible economic impacts of controlling cadmium emissions. It appears that the options are under local control and are based on local risk and socioeconomic analyses, as well as public workshops and hearings. The enforcement mechanism is via operating permits. Thus, the process is primarily directed towards site-specific evaluations and development of further regulatory tools, rather than being enforceable levels in and of themselves.


In the exposure modeling process, non-inhalation pathways should be considered for a number of substances (specified in Table III-5 in CAPCOA, 1993). Cadmium is one of the substances that require non-inhalation modeling. In the California EPA exposure and health assessments, it was acknowledged that exposure pathways other than air (i.e., water and food) were possible but that, due to the lack of quantitative information and the predominance of airborne exposure, other exposure pathways were not considered in the development of the guideline.


None


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10.4 Agency-Specific Summary: New York State


Cadmium

2. Agency:

New York State


The recommended 1-hour average is 0.2 μg/m3. The recommended annual average is 0.0005 μg/m3 based on a human-based unit risk estimate 2.0×10-3 (0.002) tumours per μg/m3. Air concentrations corresponding to excess human lung cancer risk levels of 1×10-5 and 1×10-6 for lifetime exposures are 0.005 and 0.0005 μg Cd/m3 respectively.

4. Application:

". . . they are primarily intended for use in conjunction with the permitting authority and regulatory concerns found in 6NYCRR Parts 200, 201, 212 and 257." (p. 1, NYDEC, 1991.) These regulations refer specifically to construction and operation (Certificate to Operate) permits for any sources of air contamination. Rather than being employed as legally enforceable, ambient air quality standards, the guidelines are to be employed to aid in the regulatory decision-making process. This process includes the classification of chemicals into groups of high, moderate and low toxicity. The regulatory screening process considers the toxicity classification and the emission rate potential from a facility. An air emission dispersion model is also specified in the process to guide regulators in their assessment of chemical emissions from sources of interest. Both long-term and short-term effects are considered.


NYSDEC, 1991. New York State Air Guideline -1. Guidelines for the Control of Toxic Ambient Air Contaminants (Draft). New York State Department of Environmental Conservation, Albany, N.Y. 20 p. + Appendices.


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Key References:

ACGIH, 1991. Cadmium. In: Documentation Of The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs), 6th ed. American Conference of Governmental Industrial Hygienists Inc., Cincinnati, OH.

NYSDH (New York State Department of Health), 1990. Ambient Air Criteria Document: Cadmium. Bureau of Toxic Substances Assessment New York State Department of Health, Albany, N.Y.



The scientific documents prepared by New York State employed peer-reviewed data and models, as well as the professional judgments of its scientific staff. There are opportunities for public comment on guidelines and the guideline development process, but specific information on the process for cadmium was not presented in the available documentation.


Current


NYSDEC (1991) has classified cadmium as a compound of high toxicity based on its carcinogenicity. The short-term guideline of 0.2 μg/m3 was developed by dividing the proposed 1990 American Conference of Governmental and Industrial Hygienists' occupational standard for the respirable fraction of cadmium-containing dust, 2.0 μg/m3, by 10. The short-term guideline is intended to protect the public from acute (immediate) adverse effects. It should be noted that the occupational guideline actually adopted in 1991 was 50 μg/m3 for all dusts and fumes (ACGIH, 1991).

Non-carcinogenic risk assessments for chronic exposure of the general population to cadmium may be based on renal effects observed in humans and animals. A renal cortex concentration of 40 μg/g cadmium, which corresponds to a daily uptake of 2.9 μg cadmium, is associated with a 0.1% (or less) probability that renal dysfunction will occur among sensitive individuals. This value is used for estimating an ambient air limit of 0.02 μg Cd/m3, which should limit the


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average daily intake of cadmium for all sources to less than 2.9 μg (NYSDH, 1990).

There is limited evidence in humans and sufficient evidence in animals that cadmium compounds are carcinogenic by the inhalation route of exposure. Based on the data on laboratory rats exposed by inhalation, NYSDH (1990) calculated a unit risk of 1.0×10-1 and 0.5×10-1 tumours per μg/m3. An estimate for the 95% lower confidence limit on the ambient air concentration of cadmium that corresponds to an excess human lung cancer risk of 1×10-6 after lifetime exposure to cadmium is 0.00001 µg Cd/m3. Cancer of the respiratory tract has also been observed in rats chronically exposed to cadmium chloride aerosols. In addition, preliminary results from a long-term inhalation study in rats exposed to CdCl2, CdO, CdSO4 and CdS indicate that all of these cadmium compounds induce lung tumours.

Based on the available data, it is prudent to consider all forms of cadmium as potential human carcinogens by the inhalation route of exposure. An increased risk of respiratory cancer has been observed among cadmium production workers exposed primarily to cadmium oxide dusts. The unit risk for cadmium, based on an analysis of the human epidemiological data in Thun et al. (1985), was calculated to be 2.0×10-3 (0.002) tumours per μg/m3 (NYSDH, 1990). A best estimate of the air concentration of cadmium that corresponds to an excess human lung cancer of 1×10-5 and 1×10-6 after lifetime exposure is 0.005 and 0.0005 μg Cd/m3 respectively. According to (NYSDH, 1990), the quantitative risk estimate derived from human data was based on a well-conducted epidemiology study, with reasonable exposure estimates and a sufficient follow-up period to detect an effect. Human-based risk estimates are preferred over animal-based estimates because of the quality of these data (NYSDH, 1990).


A specific computer model and guidance manual are provided for use of the guidelines in impact screening analyses as employed in the permitting process. The latest version of Appendix B of the New York State Air Guide -1 is dated April 4, 1994.


Considers human airborne exposure only


None


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10.5 Agency-Specific Summary: The Commonwealth of Massachusetts


Cadmium

2. Agency:

Commonwealth of Massachusetts


A 24-hour ceiling limit is 0.003 μg/m3, based on the threshold effects exposure limit. The allowable ambient limit (AAL) is 0.001 μg/m3 for an annual (1 year) averaging time and is based on consideration of carcinogenic effects.

4. Application:

". . . the Division of Air Quality Control, which is responsible for implementing the Department's air programs, plans to employ the AALs in the permitting, compliance, and enforcement components of the Commonwealth's air program in general, and the air toxics program in particular." (Commonwealth of Massachusetts, 1990, Volume 1, pg. ix). The primary goal is to "protect the public health and welfare from any air contaminant causing known or potentially injurious effects." The ambient air levels developed in this process should not be considered legally enforceable, air quality standards since they deal only with health-related matters and contain no consideration of technological, economic or enforcement concerns. Rather, they should be employed as guidelines in the development of subsequent regulatory action which does contain a broad consideration of all relevant concerns.


CMDEP, 1990. The Chemical Health Effects Assessment Methodology and the Method to Derive Allowable Ambient Limits, Volumes I and II. Commonwealth of Massachusetts, Department of Environmental Protection, Boston, MA.

Key Reference(s):

ACGIH, 1991. Cadmium. In: Documentation Of The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs), 6th ed. American Conference of Governmental Industrial Hygienists Inc., Cincinnati, OH.


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US EPA (United States Environmental Protection Agency), 1985. Updated mutagenicity and carcinogenicity assessment of cadmium. Addendum to the health assessment document for cadmium (May, 1981). National Technical Information Services, Springfield, VA, as cited in US EPA, 1995.


Peer-reviewed scientific research data, analyses and evaluations from various sources, including a variety of public and government agencies from around the world, and the published scientific literature, were employed in the development of these values. Specifically, evidence from the International Agency for Research on Cancer (IARC), the American National Toxicology Program (NTP) and the US EPA was employed. As guidelines, the process used and values generated were not subjected to the extensive review and consultation that air quality standards would be subjected to, but external peer reviews were carried out, and public input was solicited through at least two public meetings on the Massachusetts methodology and guideline document.


Current. Although guideline values are periodically updated, revisions to the current value for cadmium are not under consideration (D. Manganaro, Massachusetts Department of Environmental Protection, pers. comm.).


A regulation development system incorporating adjustments for exposure and a number of safety factors to address various types of uncertainties was generated both for carcinogens and non-carcinogens.

The 24-h ceiling limit of 0.003 μg/m3 is based on the threshold effects exposure limit (TEL) methodology. The TEL is derived from the most appropriate occupational limit (MAOL), which is selected from the occupational limits proposed by NIOSH, ACGIH and OSHA, in this case the ACGIH. The initial MAOL of 10 μg/m3 (the 1987-1990 ACGIH TLV) was divided by 4.2 to adjust exposure from a 40-h week to continuous weekly exposure, by a factor of 1.75 to adjust from an adult to a child, and by a factor of 10 to account for the uncertainty associated with high-risk groups. Since the toxicity data was judged to be adequate, an additional uncertainty factor of 10 was not applied. This generated an adjusted MAOL of 0.0136 μg/m3. The final TEL was obtained by taking the


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adjusted MAOL and dividing by a threshold effect uncertainty factor (TEUF), zero in this case, and adjusting to an assumed air source factor of 20% (ambient air is assumed to represent 20% of the total exposure) by dividing by 5.

Massachusetts cited the US EPA (US EPA, 1985b), which derived a unit risk value for cadmium of 1.8×10-3 per μg/m3, based on a study of respiratory cancer in smelter workers (Thun et al., 1985). Although Massachusetts used the same unit risk values as the USEPA, they proposed a slightly different value for their air quality guideline that the value developed by US EPA for their cancer risk estimate - 0.0006 versus 0.001 μg/m3. This appears to be a result of differences in mathematical rounding procedures. CMDP (1991) adopted the US EPA unit risk for use in risk assessment of inhalation exposure and concluded that, because there was no basis on which to distinguish the carcinogenic potency for different chemical forms of cadmium, it would be applied to total airborne cadmium. In addition, they note that the available data suggest that the carcinogenic potency of ingested cadmium is at least 50-fold less than by inhalation exposure and, therefore, the unit risk value cited should not be used to derive unit risk values for other routes of exposure.


The primary objective of the process is the protection of public health. The Massachusetts system uses hazard assessment only and does not use the number of exposed individuals as a criterion for regulatory action. Furthermore, the selection of the AAL is based on the most sensitive effect. The US EPA's cancer unit risk values (US EPA, 1985b) and the ACGIH occupational TLV values were adopted for regulation development purposes. For carcinogens, a maximum allowable increase in risk associated with exposure to a chemical was set at 1×10-6 for a 70-year lifetime.


A generic allowance was made for contributions from sources other than respiration: "A relative source contribution factor of 20% is also included to account for sources other than air." (CMDEP, 1990, pg. viii).


No information


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11.0 Acronyms, Abbreviations and Definitions

AAL Allowable Ambient Level (Massachusetts)

AAQC Ambient Air Quality Criteria - used by the Ontario Ministry of Environment to define the potential for causing an adverse effect

ACGIH American Conference of Governmental Industrial Hygienists - a non-governmental organization which establishes occupational safety exposure limits for workers

AGC Annual Guideline Concentration (New York State)

ATSDR Agency for Toxic Substances and Disease Registry - an agency of the US Department of Health & Human Services

CAPCOA California Air Pollution Control Officers Association

CAS Chemical Abstracts Service - ascribes a unique, identification (registry) number to each chemical to help clarify multiple listings for the same chemical structure

CEPA Canadian Environmental Protection Act

EC European Commission.

GLC Ground Level Concentration - the concentration of contaminant predicted by dispersion modelling

HEAST Health Effects Assessment Summary Tables - prepared by US EPA’s Office of Health and Environmental Assessment. HEAST contains risk assessment information on chemicals that have undergone reviews, although generally not as extensive as the reviews conduced under IRIS

HEC Human Equivalent Concentration

IARC International Agency for Research on Cancer

IRIS Integrated Risk Information System - a database published by the US EPA containing risk assessment information on a wide range of chemicals


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IRSL Initial Risk Screening Level - a limit corresponding to a one in a million lifetime risk of cancer used by Michigan for screening new sources of emissions

ITSL Interim Threshold Screening Level - similar to the IRSL, however, derived from the RfC for non-carcinogens

LC50 The concentration of a substance in the medium (eg., air, water, soil) to which a test species is exposed, that will kill 50% of the population of that given species

LD50 The dose of a substance given to a test species, that will kill 50% of the population of that given species

LOAEL Lowest-Observed-Adverse-Effect Level

LOEL Lowest-Observed-Effect Level

MAC Maximum Acceptable Concentration

MACT Maximum Achievable Control Technology

µg a microgram, one millionth of a gram

mg a milligram, one thousandth of a gram

MRL Minimal Risk Level - a term used by ATSDR, which defines a daily exposure [either from an inhalation or oral route] not likely to induce adverse non-carcinogenic effects within a given time period, ie., acute, intermediate, or chronic

MOE Ontario Ministry of the Environment; between 1993 and 1997 known as MOEE or Ontario Ministry of Environment and Energy

ng nanogram (1 × 10-9 or one billionth of a gram)

NIEHS National Institute of Environmental Health Sciences (USA)

NIOSH National Institute for Occupational Safety and Health (an agency of the US Department of Health & Human Services)

NOAEL No-Observed-Adverse-Effect Level

NOEL No-Observed-Effect Level


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NPRI National Pollutant Release Inventory

NTP National Toxicology Program (USA)

OEHHA Office of Environmental Health Hazard Assessment (California EPA)

OEL Occupational Exposure Level

OSHA Occupational Safety and Health Administration - a branch of the US Dept of Labour

PEL Permissible Exposure Limit (OSHA air standard)

POI Point of Impingement - used in conjunction with dispersion modelling to define the area in which the maximum ground level concentration (GLC) of a contaminant is predicted to occur

ppb parts per billion

ppm parts per million

REL Either ‘Reference Exposure Level’ as used by the California EPA which defines the concentration at or below which no adverse health effects are expected in the general population or ‘Recommended Exposure Limit’ used by both NIOSH and ATSDR

RfC Reference Concentration - an estimate of a daily inhalation exposure not likely to induce deleterious non-cancer health effects during a lifetime

RfD Reference Dose - an estimate of a daily exposure dose not likely to induce adverse health effects during a lifetime

RTECS Registry of Toxic Effects of Chemical Substances - database maintained by NIOSH

SGC Short-term Guideline Concentration (New York State)

STEL Short-term Exposure Limit

TC Tolerable Concentration - used by Health Canada to define the airborne concentration to which a person can be exposed for a lifetime without deleterious effects (for non-carcinogens)


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TC05 Tumorigenic concentration - the concentration of a contaminant in air generally associated with a 5% increase in incidence or mortality due to tumours

TD05 Tumorigenic dose - the total intake of a contaminant generally associated with a 5% increase in incidence or mortality due to tumours

TLV Threshold Limit Value - an exposure concentration that should not induce an adverse effect in a work environment

TWA Time-Weighted-Average - allowable exposure averaged over an 8-hour workday or 40-hour work week

US EPA United States Environmental Protection Agency

WHO World Health Organization