human uptake of persistent chemicals from contaminated soil: pcdd/fs and pcbs

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Human uptake of persistent chemicals from contaminated soil: PCDD/Fs and PCBs Renate D. Kimbrough a , Constantine A. Krouskas a , M. Leigh Carson b, * , Thomas F. Long b , Christopher Bevan b , Robert G. Tardiff b a Center for Health Risk Evaluation P.O. Box 15452 Washington, DC 20003, United States b The Sapphire Group, Inc., 3 Bethesda Metro Center, Suite 830, Bethesda MD 20814, United States article info Article history: Received 16 April 2009 Available online 24 December 2009 Keywords: PCBs PCDD/Fs Exposure Contaminated soil Gastrointestinal uptake Soil ingestion abstract Trace amounts of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are ubiquitous in the environment. Because of industrial activity, other human activities, and acci- dents, higher concentrations of these chemicals may be present in soil, in residential and recreational areas. Human uptake of these chemicals from such soils has been assumed by regulators, and people con- tacting such soils may be concerned about potential adverse health effects. Accordingly, clean up levels have been set by state and federal agencies. Whether and to what extent humans actually take up these chemicals from soil is the focus of this review. Since humans are also exposed to PCDD/Fs and PCBs in food and air, their concentrations in these media are presented. We find that their presence in soils is unlikely to increase human body burdens. Ó 2009 Elsevier Inc. All rights reserved. 1. Introduction Much has been written about exposure of humans to soil con- taminated with chemicals, particularly those that are persistent in the environment. Concern has been raised that, during the course of everyday life, contaminated soil may provide continuing opportunities for human exposures that may be sufficiently large and long-lasting to pose health risks, such as, through hand-to- mouth activity by young children, gardening by adults, and the tracking of soil and dust into the home. Over 30 years ago, because of a 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) contamination event in Missouri, the US Centers for Disease Control and Prevention (US CDC) developed a quantita- tive ‘‘level of concern” identified as 1 ppb TCDD for residential soil (Kimbrough et al., 1984). This level was meant as a guideline below which no action need be taken and above which the situation required review to determine risk management direction. This guidance was also intended to foster development of analytical methods with appropriate limits of detection in contaminated soil; since, at the time, the detection of minuscule amounts of PCDD/Fs was in its infancy, the limit of detection was set pragmatically at 100 ppt (0.1 ppb) in soil. Since then, several reports have addressed the US CDC criteria used to set this 1 ppb ‘‘level of concern” (Paustenbach et al., 1984, 2006; Gough, 1991; Kerger et al., 2007; Pohl et al., 2007). Less has been written about PCBs, and presently the basis for some clean-up soil levels for PCBs remains unclear. Underlying the setting of the low ‘‘CDC levels of concern” for TCDD and the regulatory clean up levels set for persistent organic chem- icals such as PCDD/Fs and PCBs by the US EPA and the states is the expectation that their presence in residential soil provides not only an opportunity for human exposures but also contributes mean- ingful additions to their background body burdens. Despite the many reports that discuss the plausibility of this transfer from soil to body burden, no evaluation has specifically and systematically attempted to determine in detail whether per- sistent chemicals such as PCDD/Fs and PCBs are actually taken up by people residing in contaminated areas and add to their body burdens, and, if so, to what degree. To address this consideration, this paper evaluates relevant past human exposures and more re- cent data focusing on soil concentrations and levels in human ser- um or adipose tissue to elucidate the magnitude of contribution of contaminated soil to the overall systemic exposure of humans to PCDD/Fs and PCBs. To understand the significance of some of the soil data for PCDD/Fs and PCBs, the reader is referred to the following way in which concentration data are sometimes reported, because diox- in-like compounds exist in the environment and in biological sam- ples as complex mixtures. Toxic Equivalency Factors (TEFs) were developed for these mixtures (Van den Berg et al., 1998, 2006): rel- ative toxicity values are assigned to a select number of congeners of PCDD/Fs and PCBs in comparison to the toxicity value of TCDD, and are based on their structure–activity relationship for binding to and activation of the aryl hydrocarbon receptor, whose activa- tion is believed to be a necessary, albeit insufficient, initial step in the development of the toxicity of TCDD and, by inference, of 0273-2300/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2009.12.005 * Corresponding author. Fax: +1 301 657 8558. E-mail addresses: [email protected] (R.D. Kimbrough), ckrouskas@ gmail.com (C.A. Krouskas), [email protected] (M. Leigh Carson), cjb@ thesapphiregroup.com (C. Bevan), [email protected] (R.G. Tardiff). Regulatory Toxicology and Pharmacology 57 (2010) 43–54 Contents lists available at ScienceDirect Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph

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Regulatory Toxicology and Pharmacology 57 (2010) 43–54

Contents lists available at ScienceDirect

Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier .com/locate /yr tph

Human uptake of persistent chemicals from contaminated soil: PCDD/Fs and PCBs

Renate D. Kimbrough a, Constantine A. Krouskas a, M. Leigh Carson b,*, Thomas F. Long b, Christopher Bevan b,Robert G. Tardiff b

a Center for Health Risk Evaluation P.O. Box 15452 Washington, DC 20003, United Statesb The Sapphire Group, Inc., 3 Bethesda Metro Center, Suite 830, Bethesda MD 20814, United States

a r t i c l e i n f o a b s t r a c t

Article history:Received 16 April 2009Available online 24 December 2009

Keywords:PCBsPCDD/FsExposureContaminated soilGastrointestinal uptakeSoil ingestion

0273-2300/$ - see front matter � 2009 Elsevier Inc. Adoi:10.1016/j.yrtph.2009.12.005

* Corresponding author. Fax: +1 301 657 8558.E-mail addresses: [email protected] (

gmail.com (C.A. Krouskas), [email protected] (C. Bevan), rgt@thesapphiregro

Trace amounts of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and polychlorinated biphenyls(PCBs) are ubiquitous in the environment. Because of industrial activity, other human activities, and acci-dents, higher concentrations of these chemicals may be present in soil, in residential and recreationalareas. Human uptake of these chemicals from such soils has been assumed by regulators, and people con-tacting such soils may be concerned about potential adverse health effects. Accordingly, clean up levelshave been set by state and federal agencies. Whether and to what extent humans actually take up thesechemicals from soil is the focus of this review. Since humans are also exposed to PCDD/Fs and PCBs infood and air, their concentrations in these media are presented. We find that their presence in soils isunlikely to increase human body burdens.

� 2009 Elsevier Inc. All rights reserved.

1. Introduction the basis for some clean-up soil levels for PCBs remains unclear.

Much has been written about exposure of humans to soil con-taminated with chemicals, particularly those that are persistentin the environment. Concern has been raised that, during thecourse of everyday life, contaminated soil may provide continuingopportunities for human exposures that may be sufficiently largeand long-lasting to pose health risks, such as, through hand-to-mouth activity by young children, gardening by adults, and thetracking of soil and dust into the home.

Over 30 years ago, because of a 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) contamination event in Missouri, the US Centersfor Disease Control and Prevention (US CDC) developed a quantita-tive ‘‘level of concern” identified as 1 ppb TCDD for residential soil(Kimbrough et al., 1984). This level was meant as a guideline belowwhich no action need be taken and above which the situationrequired review to determine risk management direction. Thisguidance was also intended to foster development of analyticalmethods with appropriate limits of detection in contaminated soil;since, at the time, the detection of minuscule amounts of PCDD/Fswas in its infancy, the limit of detection was set pragmatically at100 ppt (0.1 ppb) in soil. Since then, several reports have addressedthe US CDC criteria used to set this 1 ppb ‘‘level of concern”(Paustenbach et al., 1984, 2006; Gough, 1991; Kerger et al., 2007;Pohl et al., 2007). Less has been written about PCBs, and presently

ll rights reserved.

R.D. Kimbrough), ckrouskas@m (M. Leigh Carson), [email protected] (R.G. Tardiff).

Underlying the setting of the low ‘‘CDC levels of concern” for TCDDand the regulatory clean up levels set for persistent organic chem-icals such as PCDD/Fs and PCBs by the US EPA and the states is theexpectation that their presence in residential soil provides not onlyan opportunity for human exposures but also contributes mean-ingful additions to their background body burdens.

Despite the many reports that discuss the plausibility of thistransfer from soil to body burden, no evaluation has specificallyand systematically attempted to determine in detail whether per-sistent chemicals such as PCDD/Fs and PCBs are actually taken upby people residing in contaminated areas and add to their bodyburdens, and, if so, to what degree. To address this consideration,this paper evaluates relevant past human exposures and more re-cent data focusing on soil concentrations and levels in human ser-um or adipose tissue to elucidate the magnitude of contribution ofcontaminated soil to the overall systemic exposure of humans toPCDD/Fs and PCBs.

To understand the significance of some of the soil data forPCDD/Fs and PCBs, the reader is referred to the following way inwhich concentration data are sometimes reported, because diox-in-like compounds exist in the environment and in biological sam-ples as complex mixtures. Toxic Equivalency Factors (TEFs) weredeveloped for these mixtures (Van den Berg et al., 1998, 2006): rel-ative toxicity values are assigned to a select number of congenersof PCDD/Fs and PCBs in comparison to the toxicity value of TCDD,and are based on their structure–activity relationship for bindingto and activation of the aryl hydrocarbon receptor, whose activa-tion is believed to be a necessary, albeit insufficient, initial stepin the development of the toxicity of TCDD and, by inference, of

44 R.D. Kimbrough et al. / Regulatory Toxicology and Pharmacology 57 (2010) 43–54

other dioxin-like compounds. The concentration of each congeneris multiplied by its respective TEF value and summed to give a sin-gle TCDD equivalent value or Toxic Equivalent (TEQ).

The background levels of these substances in various environ-mental media—food, air, water, and soil—are also noted to placeinto context their contribution relative to the contribution fromcontaminated soil to overall exposure. For these substances, oraland inhalation exposures are the dominant routes of intake inthe general population, including those who live on contaminatedsoil. When considering exposure of individuals to contaminatedsoil, inhalation results from dust being disturbed from playing,yard work, or other common activities, while oral exposure mayresult from children ingesting soil. The uptake of PCDD/Fs viaplants is not considered typical (ATSDR, 1998, 2000) because (1)plants do not assimilate these complex molecules and (2) mostfood preparers in advanced cultures are advised to fully clean veg-etables of highly lipid soluble chemical residues and foreign parti-cles prior to food preparation. Dermal absorption is considered aminor contributor to body burdens of the general population,and is not discussed in this review.

This evaluation examines the data for PCDD/Fs and PCBs sepa-rately, and subsequently seeks to formulate generalizations appli-cable to both classes combined.

This paper is not intended to address how or to what degree thefindings may influence remediation approaches; however, perhapsthe findings may be examined as part of such considerations.

2. Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs)

To test the hypothesis that residential soil levels of PCDD/Fs arerelated to human body burdens (expressed as levels in serum oradipose tissue), three data sets or case studies were selected: (1)Missouri (US), (2) Seveso (Italy), and (3) Michigan (US). In additionto the three primary data sets, a small data set from Germany con-sisting of the levels of PCDD/Fs in 12 subjects living in a residentialarea where the soil was highly contaminated by PCDD/Fs and othersubstances is also presented.

2.1. Missouri (US) case study

A waste oil dealer sprayed salvage oil mixed with industrialwaste containing TCDD and 2,4,5-trichlorophenol on roads, a farm,and on riding arenas in 1971. After extensive laboratory investiga-tion in 1974, the US CDC identified TCDD in a soil sample collectedin 1971 from a riding arena at a concentration of 32–33 ppm(Carter et al., 1975). When the investigation was reopened in1974, a few people from the most highly contaminated riding are-na reported having had skin lesions; however, the nature of thoselesions could not be determined since they were no longer present.A child that had played in the highly contaminated arena devel-oped a hemorrhagic cystitis, a condition not known to be attrib-uted to TCDD. Despite the high concentrations of TCDD in soil(sufficient to kill 48 of 85 horses exposed to the contaminated are-na), no serious human health effects were observed among resi-dents. Since the cause of this outbreak was initially unknown, noattempts were made to measure TCDD in human blood or adipose

Table 1Adipose TCDD levels (ppt) in control and exposed population (Missouri).

Controls Total exposed Re

N 57 39 8Range (geometric mean) 1.4–20.2 (6.4) 2.8–750 (21.8) 5.0Mean age (years) 52.6 44.3 42% Men 35.1 61.5 37

Modified from Hoffman and Stehr-Green (1989).

tissue. At that time, reliable methods to measure blood levels werealso unavailable at US CDC. Later TCDD was determined in adiposetissue obtained by open biopsy (Table 1) (Hoffman and Stehr-Green, 1989).

In mid-1982, many more areas in Missouri were found to havebeen similarly contaminated with TCDD mixed in salvage oil. As ofthe late 1980s, a total of 44 additional sites were confirmed as hav-ing at least 1 ppb of TCDD in soil, and up to 2200 ppb were found insoil in isolated areas; however, most detected levels ranged fromone to several hundred ppb. Several health studies of the contam-inated residential areas found no unusual adverse health effects.Initial hypersensitivity skin test results suggested that some ofthe exposed individuals were anergic; however, this conditioncould no longer be demonstrated on follow-up (Hoffman and Ste-hr-Green, 1989). No serum samples were available for analysis ofTCDD in this study.

In 1987, the Missouri State Health Department developed a cen-tral listing of persons who had a high risk of potential exposure.Adipose tissue samples from individuals in the central listing groupand from a comparison group with no known exposure to TCDDwere analyzed. The mean age of the comparison group was52.6 years, and 35% were men. The arithmetic mean TCDD concen-tration in this group of 57 adults was 7.4 (1.4–20.2) ppt, whileeight persons of similar age with recreational exposure to the rid-ing arenas had mean levels of 90.8 (5–577) ppt. The individual withthe highest adipose TCDD concentration (577 ppt) after recrea-tional exposure was actually riding in the arena during the spray-ing event; therefore, the exposure was primarily via the air. In 16residentially exposed individuals with a mean age of 39.7 years,the mean was 21.1 (2.8–59.1) ppt TCDD. Fifteen individuals occu-pationally [worked in factory/truck terminal where grounds hadbeen sprayed with TCDD-contaminated oil] exposed with a meanage of 50 years had mean TCDD levels of 136 (3.5–750) ppt in theiradipose tissue (Table 1). The adipose TCDD concentration in the ex-posed groups was significantly increased when compared to theunexposed group (Hoffman and Stehr-Green, 1989; Pattersonet al., 1986). Even though the concentrations in soil in many areaswere quite high (1–2200 ppb in many residential areas and up to33,000 ppb initially in a riding arena) at the time of analysis in1985, TCDD adipose tissue levels in persons from TCDD contami-nated residential areas were not as elevated as those from individ-uals who had been recreationally exposed. Except for occupationalexposure, no attempt was made to determine potential confound-ers including other sources, age, gender, and body weight.

This case is unique in that the TCDD was mixed with oil, whichmay have made it more bioavailable to humans and the horses(possible absorption of TCDD through the foot pads of the horsesand ingestion of soil-contaminated straw in the stables). Sincethe waste oil with the TCDD was sprayed, the contamination wasrelatively uniform, rather than being spotty as is usually the casein other soil contamination scenarios. The person with the highestadipose tissue level after recreational exposure (577 ppt) at theriding arena was determined to have been exposed, during andafter spraying, to soil containing 33,000 ppb TCDD for monthsand somewhat lower concentrations for years thereafter. Whatrole the presence of 2,4,5-trichlorophenol played is unclear.

creational exposed Residential exposed Occupational exposed

16 15–577 (24.8) 2.8–59.1 (15.3) 3.5–750 (29.8).1 39.7 50.3.5 43.8 93.3

R.D. Kimbrough et al. / Regulatory Toxicology and Pharmacology 57 (2010) 43–54 45

This case study provides limited support for judging the nat-ure and magnitude of the contribution of TCDD present in soiland concentrations in human adipose tissue and serum. Basedon the data from the Missouri State Health Department, theTCDD concentrations in soil (33 ppm; 33,000,000 ppt) can becompared to those in human serum of unexposed individuals(average 7.4 ppt), recreationally exposed individuals (average91 ppt), and occupationally exposed individuals (average136 ppt). The recreationally exposed individuals were also ex-posed during spraying, and the occupationally exposed individu-als had other exposures as well which were the predominantsources for their higher body burden.

2.2. Seveso (Italy) case study

This situation is also relatively unique. Initially, exposure wasvia air, particularly for children who were playing outside at thetime a reaction vessel accidentally released TCDD in 1976. Theexposures were sufficiently large to kill birds, rabbits, and chickensa few days after the incident. A few children who had been directlyexposed to airborne contaminated dust complained of nausea anddeveloped skin lesions pathogenomonic of TCDD exposure. Grasssamples from a cone-shaped 900 m long area contained levels ofTCDD up to 15,840 lg/m2 (�16 ppm) surface area (Reggiani,1980). A total of 165 g of TCDD was estimated to have beenreleased to the local environment (Reggiani, 1980). The Italianauthorities divided the contaminated area into Zones A (180 acres),B (556 acres), and R (2954 acres). One to two weeks after the acci-dent, 736 people residing in Zone A were evacuated initially fromthe highly contaminated area (Zone A; average concentrations ran-ged from �15 to �580 ppb), while no evacuation occurred in ZoneB (average contamination of �3 ppb) or Zone R (average contami-nation of non-detect to �0.5 ppb). After 65 acres of Zone A werecleaned up, 511 evacuated people were allowed to return to theirhomes (Reggiani, 1980). Since the 1976 accident, mortality andmorbidities studies were conducted on the population with expo-sure groups defined by the individual’s zone of residence. However,these studies suffer from poor assessment of exposure, and poten-tial confounders were not evaluated. Additionally, as the popula-tion increased in the municipalities over time because peoplemoved into the area, they were included in the morbidity and mor-tality studies. Between the 10-year (Bertazzi et al., 1989) follow-upand the 20-year follow-up of the mortality study (Bertazzi et al.,2001), the population included in the study increased by 31% inZone A, 34% for Zone B, and by 32% in Zone R. People also movedbetween the different zones. Addition of such large groups of peo-ple 10 years after the accident brings to surface some serious studyvalidity and reliability issues. Most of the additional people hadmuch less or no exposure since, in the interim, extensive remedia-tion was performed and they were not part of the initial cohort.

Grass and soil samples were collected after the accidentalrelease of TCDD in zone A, the closest to the chemical manufactur-ing plant; the highest concentrations in soil ranged from 92 to5477 ppb, some non-detects were also reported (Reggiani, 1980).Because of the contribution by several routes of exposure, suchas levels on grass, in soil, in the air, and in or on home-growndomestic animals and vegetables in the early weeks after the acci-dent, direct comparisons between TCDD levels in soils and TCDDbody burdens (serum and adipose tissue) could not be made forthat time period by Mocarelli et al. (1991).

At the time of the incident, serum samples were collected fromthe population, stored, and later analyzed at the US CDC. The find-ings were reported on a lipid-adjusted basis. In children, serumlevels in residents of zone A ranged from 1690 to 56,000 ppt;and in adults from zone A, serum levels ranged from 828 to10,000 ppt (Mocarelli et al., 1991).

Although TCDD soil levels in Missouri were equal to or higherthan those in Seveso, serum and adipose tissue levels of TCDD weremuch higher in the Seveso population suggesting that soil inSeveso was not the primary contributor to exposure. The large air-borne release of TCDD from the 2,4,5-trichlorophenol reactor mayhave provided an acute inhalation dose that was overwhelminglygreater than that from ensuing consumption of locally grown pro-duce on which TCDD had been directly deposited subsequent tothe inhalation exposure.

If soil had been the primary source of TCDD exposure, the serumTCDD levels in Missouri and Seveso should have been similar.Therefore, the Seveso case study is not relevant and provides nosubstantial support for judging the nature or magnitude of the con-tribution of PCDD/Fs present in soil and concentrations in humanserum.

2.3. Michigan (United States) case study

An extensive dioxin exposure study was reported by investiga-tors of the University of Michigan (UMDES; University of MichiganSchool of Public Health, 2006; Garabrant et al., 2009). The investi-gators selected a random sample of Michigan residents in the fol-lowing jurisdictions: Jackson, Calhoun, Midland, SaginawCounties and Williams Township in Bay County. Jackson and Cal-houn Counties represented comparison areas with no knownindustrial sources of PCDD/F contamination. Midland and Saginawresidents lived in an area with potential past exposures to PCDD/Femissions from the Dow Chemical Company plant in Midland andexposure to PCDD/Fs in soil.

To be eligible for the study, residents had to be at least 18 yearsold, and had to have lived at their current address for at least fiveyears. A questionnaire was administered to participants to obtaindemographic and health data as well as information on diet, recre-ational activities, occupation, and military history. Participantswere also asked to provide an 80 milliliter blood sample and toconsent to sampling of household dust and soil around theirhomes. The authors collected blood from 946 participants, tested766 properties, and administered a questionnaire to 1324 individ-uals. The serum levels were quantified on a lipid basis, and shouldessentially be equal to adipose tissue levels (Patterson et al., 1988).

Garabrant et al. (2009) found that older people and males withhigher body mass indices had higher PCDD/F levels expressed asTEQs than individuals who were underweight (lower body massindices) [values not stated]. This finding is consistent with the lipo-philic nature of these compounds (Milbrath et al., 2009). They alsonoted that women under 40 had lower levels than men, whereaswomen over 40 had higher levels than men [values not stated](University of Michigan School of Public Health, 2006; Garabrantet al., 2009).

A recent report on the Michigan data gives serum concentra-tions for five geographically defined groups: (1) Control [Jacksonand Calhoun counties]; (2) Floodplain [Tittabawassee River flood-plain]; (3) Near Floodplain [areas next to the floodplain in Midlandand Saginaw counties]; (4) Midland Plume [area downwind of theDow Chemical plant]; and (5) Midland/Saginaw [other areas in theMidland and Saginaw counties]. The median TEQ level, using the1998 TEF values as stated in Van den Berg et al. (1998), of PCDD/Fs in the serum of the Control population was 25 (5–150) ppt ona lipid-adjusted basis; for people living in the Floodplain, themedian was 32 (5–238) ppt lipid-adjusted; in the Near Floodplainpopulation, the median 1998 TEQ level was 29 (5–210) ppt lipid-adjusted; the median was 24 (7–97) ppt lipid adjusted and 28(5–129) ppt lipid-adjusted in the Midland Plume and Midland/Sag-inaw populations, respectively (University of Michigan School ofPublic Health, 2006). Using total UMDES data, the mean serumPCDD TEQ level based on the 1998 TEF values was 15.2 ppt

46 R.D. Kimbrough et al. / Regulatory Toxicology and Pharmacology 57 (2010) 43–54

lipid-adjusted, while it was 4.9 ppt lipid-adjusted for PCDFs (Honget al., 2009).

Using the updated 2005 TEF values as described in Van den Berget al. (2006), the median lipid adjusted TEQ serum levels of PCDD/Fs in the same individuals was 19 (5–109) ppt lipid-adjusted [Con-trol], 23 (5–210) ppt [Floodplain], 22 (4–154) ppt [Near Flood-plain]; 17 (4–79) ppt [Midland Plume], and 21 (4–107) ppt[Midland/Saginaw] (University of Michigan School of PublicHealth, 2006). The mean serum PCDD concentration when usingtotal UMDES data based on the 2005 TEF values was 15.3 ppt li-pid-adjusted, while it was 3.6 ppt lipid-adjusted for PCDFs (Honget al., 2009).

Overall, these median TEQ blood levels are in the range of med-ian levels of the general US population (24 ppt lipid-adjusted)(CDC, 2005; University of Michigan School of Public Health,2006), whether the 1998 or 2005 WHO TEF values are applied(Van den Berg et al., 1998, 2006). However, the limits of detectionfor the US CDC data are higher than for the UoM data making sideby side comparisons somewhat imprecise. Serum data from theUMDES showed that 64.7% of the TEQ level (based on the 2005TEF values) were contributed by PCDD congeners, while PCDFsmade up only 16.4% [PCBs contributed the remainder] (Honget al., 2009).

In many blood samples, PCDFs were below the limit of detectionof the analytical method (Hedgeman et al., 2009), while this wasnot the same for the PCDF congeners in soil. While demographicfactors such as age, body mass index, sex, breast feeding, smokingexplained much of the variance between dioxin serum, soil andhousehold dust data explained very little: 0.5% for TCDD and lessthan 0.01% for the other congeners, while about 4% of variance isexplained by the dietary factors (University of Michigan School ofPublic Health, 2006).

Calculations of PCDD/F TEQ levels in soil in the Michigan areawere also reported in a recent study. Using the UMDES data, meanhousehold dust and soil PCDD TEQ levels based on the 1998 WHOTEF values were determined to be 22.3 and 6.2 ppt, respectively,while mean PCDF TEQ levels were 4.9 and 8.2 ppt, respectively.When the 2005 WHO TEF values were applied to the same data,mean PCDD TEQ levels were 24.0 and 6.4 ppt in household dustand soil, respectively, while mean PCDF TEQ levels were 4.2 and6.3 ppt, respectively. It was estimated that PCDDs contributed66.8% and 54.4% to the TEQ level (based on the WHO 2005 TEF va-lue) in household dust and soil, respectively, while PCDFs made up15.6% and 32.1%, respectively [PCBs contributed the remainder](Hong et al., 2009).

Living presently in the contaminated areas was not associatedwith TEQs or any specific PCDD/F congeners. Outliers of high bloodTEQs greatly influenced some initial positive associations as, for in-stance, with garden soil. Once these eight outliers were removed,due to prolonged and frequent consumption of wild game and/orsport-caught fish both from within and outside the Saginaw–Tit-tabawasee floodplain and other types of exposure, the statisticalpositive associations were eliminated (Garabrant et al., 2009). Aperson with a TCDD blood level of 211 ppt on a lipid-adjusted basisturned out to be a ceramic hobbyist: The wet clay used for makingceramics had a TEQ level of 3190 ppt; the practice of firing the clayin unvented kilns appears to explain the elevated blood TEQ levelsrather than the TEQ levels in garden soil (Franzblau et al., 2008).

Very little, if any, correspondence was found between environ-mental levels of PCDD/F TEQs in dust and soil and the amounts ofPCDD/F TEQs in peoples’ serum once the outlier values wereexcluded (Garabrant et al., 2009). However, people who ate fish,whether store-bought, sport-caught (from both within and outsidethe Saginaw–Tittabawasee floodplain), or from a restaurant hadhigher blood PCDD/F TEQs than non-fish eaters; specifically forevery year fish was consumed, TCDD serum concentration

increased by 2.5% while the serum concentration of other PCDDcongeners increased by 1% (University of Michigan School of PublicHealth, 2006).

Consequently, the UMDES provides substantial support forjudging the nature or magnitude of the contribution of PCDD/Fspresent in soil and concentrations in human adipose tissue and ser-um. The Michigan data set is considered relevant because it closelyassociates contaminated soils and serum levels in a carefully mon-itored population, and it also takes into account background levelsof PCDD/F from populations not residing on contaminated soils andother potential exposures and demographic factors that addressthe largest contribution is from fish consumption [value not sta-ted]. These data indicate rather convincingly that soil contami-nated with PCDD/F contributes little (perhaps <1%) if any ofthese compounds to human body burden as measured by serumconcentrations.

2.4. Supplemental data from Germany

A study in Germany of a relatively small number of individuals(12) measured serum levels and associated soil concentrations ofPCDD/Fs in a residential area where the soil was highly contami-nated by PCDD/Fs and other substances (Ewers et al., 1997). Insamples taken from the top 30 cm of soil, levels of PCDD/Fs ex-pressed as TEQs ranged from 59 to 33,536 ppt; below 90 cm, theyranged from 8342 to 100,900 ppt. Six people (median age:56 years) who had lived in the area for more than 35 years andwho over many years ate produce grown on the contaminated soiland also domestic animals raised on the soil had median serumPCDD/Fs TEQ levels of 41.5 (18.0–54.6) ppt, while the median forthe unexposed comparison group was 20 (12.2–30.5) ppt. The dif-ference between these groups was statistically significant(p = 0.01). By contrast, another six people (median age: 47 years)who had lived in the area for about five years and had consumedonly minor amounts of home-grown vegetables, fruits, but noself-produced animal products, had median PCDD/Fs TEQs of 23.4(13.1–45.8) ppt, which was not significantly different from theunexposed comparison group (median of 13.9; range of 12.1–30.5 ppt). Other potential sources of exposure such as fishconsumption or occupation were not investigated, adding someuncertainty to the comparisons. However, the congener patternin house dust did not resemble the pattern found in soil: In housedust, octaCDD and octaCDF dominated, followed by heptaCDF sug-gesting that sources within the home contributed to the composi-tion of the house dust.

Consequently, for those individuals who had resided for a con-siderable time on contaminated soil, their body burdens wereslightly elevated over those of the control group. However, thiswas only statistically significant in inhabitants that consumedhome-grown animal products and vegetables, rather than onlyhome-grown produce, which is an expected finding as studies havedemonstrated that meat, dairy, and eggs contribute more to die-tary intake than vegetables and grains. Therefore, the data provideno direct evidence for the contribution of soil to human serum con-centration. Other dietary sources such as fish and demographic fac-tors were also not evaluated.

Overall from these assorted data sources, one finds that theMichigan information most strongly supports the ability to ad-dress the magnitude of contribution of PCDD/Fs in contaminatedsoils to human body burden of the compounds in these mix-tures. That contribution appears relatively small, despite theirenvironmental persistence and is negligible (61%) compared toother sources of exposure. The Missouri case provides limitedsupport for that conclusion, while the German supplementaldata remains inconclusive. The Seveso case was deemed notrelevant.

R.D. Kimbrough et al. / Regulatory Toxicology and Pharmacology 57 (2010) 43–54 47

2.5. Bioavailability

Whether PCDD/Fs in soils are actually bioavailable when hu-mans come into contact with contaminated soils is a central con-sideration. This question is particularly relevant since PCDD/Fshave been shown to be tightly bound to soil particles (Budinskyet al., 2008). Studies in laboratory animals have addressed thisquestion. These studies have shown that the oral bioavailabilityof PCDD/Fs is much less when present in soil and other solid matri-ces than when given in oil or when mixed as a solution into animalfeed. A relative oral bioavailability of approximately 80% was ob-tained in laboratory rodents given TCDD in corn oil (Dilibertoet al., 1996; Rose et al., 1976). By contrast, as shown in Table 2,the relative and absolute oral bioavailability for TCDD-contami-nated soils were only �10–40% and �10–30%, respectively. [‘‘Abso-lute bioavailability” is the amount absorbed into the bloodstreamby one or more routes of administration; ‘‘relative bioavailability”is the ratio of the amount (e.g., in soil or food) absorbed into thebloodstream to that in a reference material (e.g., corn oil or water)multiplied by 100]. This diminished bioavailability of PCDD/Fs insoil and sediments is likely due to the tendency of these com-pounds to be strongly adsorbed to soil and sediments. The typeand condition of the tested soil and/or sediment (i.e., soil agingor weathering) reduces the oral bioavailability of PCDD/Fs (Alexan-der, 2000; Koelmans et al., 2006). Other circumstances, such as thepresence of PCDD/Fs adsorbed to graphitic electrode carbon, couldbe directly controlling desorptive processes and oral bioavailability(Budinsky et al., 2008).

Budinsky et al. (2008) highlight the importance of using soilsamples from the PCDD/F-contaminated sites when determiningsite-specific oral bioavailability. As noted above, oral bioavailabil-ity of TCDD/Fs in soil is influenced by ‘‘weathering” (soil aging)and the presence of carbon or by unique manufacturing circum-stances that created the PCDD/Fs as unintentional by-products. Inaddition, Budinsky et al. (2008) also showed that oral bioavailabil-ity of PCDD/Fs from soil is species-dependent. Both rats and juve-nile swine were used to estimate oral bioavailability in two soilswith distinct congener profiles (one dominated by PCDDs and theother by PCDFs). The digestive tract of juvenile swine is structur-ally and functionally closer to that of humans than that of the rat

Table 2Bioavailability of PCDDs given in soil.

Species Site Particle size(lm)

TCDD concentratiosoil (lg/kg)

SD rats Minker Stout, MO <250 880Guinea pigs Times Beach, MO <250 770

Newark, NJ <250 880Guinea pigs Times Beach, MO NA 510

Newark, NJ NA 1400Ab rabbits Seveso, Italy 37–74 81SD rats Times Beach, MO <420 723Guinea pigs Newark, NJ NA 2280Minipigs Hamburg 100–200 27–51

GermanySD rats Urban soil at Midland, MI <250 0.13 TEQ;

0.017–0.14g

Jv swine Urban soil at Midland, MI <250 0.13 TEQ;0.017–0.14g

Abbreviations: Ab, Albino; Jv, Juvenile; NA, not applicable; NJ, New Jersey; MI, Michigana Calculated by Dow Chemical, unpublished report.b Calculated by authors of cited reference.c Shu et al. (1988) assumed 70% absolute bioavailability from corn oil.d Umbreit et al. (1986) provide these bioavailability estimates in text. No corn oil livee Range for dioxin congeners (i.e., TCDDs relative bioavailability was 2%).f Range for furan congeners (i.e., 4-PeCDFs relative bioavailability was 34.4%).g TCDD dose range taken from Ruby et al. (2002) as cited in Budinsky et al. (2008).h Budinsky et al. (2008) assumed 80% absolute bioavailability from corn oil.

(Groner et al., 1990; Kidder and Manners, 1978; Kurihara-Berg-strom et al., 1986; Miller and Ullery, 1987), and is similar to thedigestive tract of children 2–5 years of age (Moughan et al.,1992). The relative oral bioavailability in juvenile swine of PCDD/Fs from the two types of soil was between 20% and 25% on a TEQbasis compared to administration in corn oil. In rats, the relativeoral bioavailability of PCDD/Fs was higher than that in swine,approximately 37% and 60% for the two soils (on a TEQ basis),respectively (Budinsky et al., 2008). These site-specific estimatesof oral bioavailability can reduce exposure estimate uncertainties,since regulatory default guidance requires oral bioavailabilityranging from 50% to 100%.

The data from Budinsky et al. (2008) showed that predictions ofPCDD/Fs bioavailability in humans based on rat data would beoverpredictive by 2- to 3-fold. No conclusions can be made regard-ing body burden.

3. Background levels of PCDD/Fs

The following provides an overview of background levels in thegeneral environment, and as such can provide context to the valuesreported in the case studies.

PCDD/Fs are byproducts of natural processes as well as man-made chemical syntheses. US EPA (2003) has calculated ‘‘typical”background soil levels in the US: the mean rural background TEQas defined by the World Health Organization in 1998 (TEF–WHO98) was estimated to be 2.6 ppt, and the ‘‘typical” urban back-ground was estimated to be 8.8 ppt, assuming that non-detectsequal zero.

Background levels of PCDD/Fs have been found in clay in north-western Mississippi, Kentucky, and Tennessee attributed to naturalgeological processes (Ferrario et al., 2000; Fiddler et al., 2000;Gadomski et al., 2004; Hayward et al., 1999; Hayward and Bolger,2005; Holmstrand et al., 2006; Horii et al., 2008) with the averageTEQs for raw and processed samples of up to 1513 ppt dry weight.Levels of PCDFs were between 2 and 3 orders of magnitude lowerthan the PCDDs or below levels of detection.

In the US, food is the primary contributor to body burden fromPCDD/F: Over 90% of the exposure of humans to PCDD/Fs has beenestimated to occur through the diet, with the greatest contribu-

n in Relative soilbioavailability

Absolute soilbioavailability

Reference

21–45a 17–36a Lucier et al. (1986)14–19a 11–15a McConnell et al. (1984)

1.6–30b 1.3–24a Wendling et al. (1989)

33–40a 27–33a Bonaccorsi et al. (1984)53–70%a 37–49b,c (mean of 43) Shu et al. (1988)0.5–21.3b,d NA Umbreit et al. (1986)2–39.8b,e 1.6–31.8a,e Wittsiepe et al. (2007)22.8–42.2b,f 18.3–33.8a,f

35b 28b,h Budinsky et al. (2008)

18–22b 15–18b,h Budinsky et al. (2008)

; MO, Missouri; SD, Sprague–Dawley; TEQ, toxic equivalence.

r data were provided.

48 R.D. Kimbrough et al. / Regulatory Toxicology and Pharmacology 57 (2010) 43–54

tions coming from meat, dairy, and local freshwater fish products(EPA, 2003; IOM, 2003). In the US, PCDD/F intake was estimatedby the US EPA at 0.6 pg TEQ/kg in 2000. Charnley and Doull(2005) estimated that the mean PCDD/F intake for the US popula-tion in 2002 was about 0.4 pg TEQ/kg body weight per day and1.2 pg/kg body weight per day at the 95th percentile. The mean in-take for children is higher, ranging from 0.9 to 1.2 pg TEQ/kg bodyweight. About 50% of the daily dietary TEQ intake by the general USpopulation was attributed to meat and dairy; and fish comprisedabout 6%. These intake estimates are comparable to the recentUS FDA analysis of dietary PCDD/F exposure (South et al., 2004).The US EPA’s recent exposure and human health reassessment ofdioxins (EPA, 2003) included mean dietary intake estimates thatwere similar to those determined by Charnley and Doull (2005)(i.e., 0.23–0.24 pg TEQ/kg-day, respectively).

In the US, PCDD/Fs in air contribute relatively little to humanbody burdens. Smith et al. (1990) measured PCDD/Fs in atmo-spheric samples of cities in the State of New York, and reported lev-els between 3.0 and 21.6 pg/m3 of total PCDD/Fs. Cleverly et al.(2007) measured the atmospheric concentrations of PCDD/Fs inrural and remote areas of the US between June 1998 and December2002 and reported levels, expressed as TEQ values in air, in the lowfemtogram/m3 range. Based on data from various studies, US EPA(2003) reported that the mean TEQ concentration was 0.013 pg/m3 for rural sites and 0.12 pg/m3 for urban areas.

Since PCDD/Fs are highly lipid soluble, they may be present inno more than extremely low concentrations (ppq) in ground- andsurface-water as well as treated tap water. In general, PCDD/Fshave seldom been detected in drinking water at ppq levels andhigher (EPA, 2003). These compounds may contaminate surfaceand ground water in areas with point sources; and, when theydo, they usually adhere to soil or sediment particles thereby reduc-ing their mobility. Their presence has not been reported in munici-pal drinking water, perhaps because of the effectiveness offiltration at removing contaminant-containing particulates (EPA,2003).

PCDDs/Fs are persistent mixtures in the environment (Kimb-rough and Krouskas, 2003). Furthermore, their human body bur-dens reflect a balance between past and present uptake frommultiple sources and subsequent slow elimination (EPA, 2003;Kimbrough and Krouskas, 2003). In US studies conducted duringthe 1990s, PCDD/F levels in adipose tissue ranged from <0.26 to1630 ppt lipid, while PCDD/F blood levels ranged from non-detectto 1000 ppt. Mean total PCDD levels in human milk in the USwere estimated to be 327 ppt in the late 1980s. In the US, the dai-ly intake of PCDD/Fs via human milk by nursing infants has de-creased from 83.1 pg TEQ/kg-d bw in the 1980s to 35–53 pgTEQ/kg-d bw in the 1990s, whereas a decline in TEQ values forPCDD/Fs in mother’s milk from 24.7 ppt TEQ in the early 1980sto 15.6 ppt TEQ in the early 1990s has been reported in Canadianwomen. In teenagers and young adults, serum lipid levels ofPCDD/Fs have also decreased in the recent past, and are fre-quently below the limits of detection. Older adults are more likelyto have measurable and higher serum lipid levels of PCDD/Fs be-cause of past exposures and perhaps because of a slower metab-olism (CDC, 2005).

4. Polychlorinated biphenyls (PCBs)

To test the hypothesis that residential soil levels of PCBs are re-lated to human body burdens (as measured in serum), data sets orcase studies from five locales were selected: (1) Massachusetts(US), (2) Indiana (US), (3) Alabama (US), (4) Michigan (US), and(5) Toronto (Canada). A review of data sets from 12 other US toxicwaste sites (Superfund sites) is also presented.

4.1. Massachusetts (US) case studies

The Massachusetts Department of Public Health (1997) as-sessed PCB exposure in the Housatonic River basin area, which in-cludes Pittsfield where a PCB capacitor plant was located. PCBlevels in soil in the floodplain area ranged from 100 ppm to lessthan 10 ppm; other areas closer to the plant had higher levels.PCB serum levels were measured in 52 residents between the agesof 18 years to 65 and above. The PCB levels of all participants ran-ged from undetected levels to 11.44 ppb (this maximum concen-tration occurred in an individual more than 65 years old). Eatingfresh water fish or gardening had little impact on PCB serum levels,as indicated by PCB serum levels among those tested being not sta-tistically different from those in the general population, evenamong people with the highest potential for non-occupationalPCB exposure.

Historically, the Acushnet River area of greater New Bedford(Massachusetts) had become heavily contaminated with PCBsdue to wastewater discharge and through the disposal of electronicequipment and manufacturing wastes in that region, resulting insome sediment samples exceeding PCB concentrations of100,000 ppm (Miller et al., 1991). Serum specimens of 391 maleand 449 female volunteers (18–64 years) in the area were analyzedfor PCBs. These volunteers had resided in this area for at least5 years. Only 1.3% of this population had fasting PCB serum levelsabove 30 ppb on a wet weight basis, the upper level of the normalrange at the time of the study; the geometric mean concentrationfor male volunteers was 4.3 (0.5–60.9) ppb and for females was 4.2(0.38–154) ppb (Miller et al., 1991). Within this population, 23subjects with serum PCB levels at or above 30 ppb were studiedfurther. The authors found that eating fish, age, and occupationalexposure—and no contact with contaminated soil—had resultedin the elevated PCB serum levels (Burse et al., 1994).

Choi et al. (2006) measured PCB levels in the cord serum of 720term infants who were born between 1993 and 1998 to mothersliving near a PCB contaminated superfund site in Massachusetts.No association was found between total PCB levels and residentialdistance from the superfund site, an unexpected finding had soilcontributed substantially to the body burden of PCBs in pregnantwomen. Similar results were observed with light and heavy PCBsand congener PCB-118. The geometric mean of total PCB levels incord serum was 0.4 (0.068–18.14) ppb.

The aforementioned cases provide evidence for judging the nat-ure or magnitude of the contribution of PCBs present in soil to hu-man PCB body burdens. The data are considered relevant becausethey closely examine PCBs in serum levels in a monitored popula-tion in close proximity to PCB-contaminated soils. Overall, thesedata suggest that soil contaminated with PCBs contribute little ifany of these compounds to human body burdens as measured byserum concentrations.

4.2. Indiana (US) case study

In Bloomington, Indiana, Baker et al. (1980) studied a popula-tion that had used sewage sludge contaminated with PCBs for gar-dening. The PCB concentration in the sludge treated soil rangedfrom 0.1 to 107.3 ppm with a mean of 17.1 ppm. The mean PCBserum levels on a wet weight basis in 91 persons using the con-taminated sludge was an average of 17.4 ppb compared with anaverage of 24.4 ppb in 23 controls.

In a follow-up study in 1987, the Agency for Toxic Substances andDisease Registry (ATSDR) evaluated the health implications of expo-sure to PCBs through PCB containing municipal sewage sludge usedin gardens and among residents living near three waste sites aroundBloomington, Indiana. PCB serum levels were measured in 995 sub-jects between the ages of 18 and 65 living in Monroe County, Indiana.

R.D. Kimbrough et al. / Regulatory Toxicology and Pharmacology 57 (2010) 43–54 49

On a wet weight basis, the mean total PCB level was 8.1 ppb in malesand 7.8 ppb in females. Approximately 3.6% of the study populationhad serum PCB levels >20 lg/L (Steele and Richter, 1992). Thesehigher levels were associated with age over 55, and 21% of the studypopulation had worked in establishments where PCBs had beenused. The range for all study participants was from 0.9 to 76.1 ppb.In spite of the potential for exposure to PCB contaminated media,individuals living in the general community were unlikely to haveincreased uptake of PCBs, based on the results of their serum PCB lev-els (Steele and Richter, 1992). Thus, ingestion of soil and/or foodgrown on PCB-contaminated soil appears to not have contributedto PCB body burdens.

This case provides limited evidence for judging the nature ormagnitude of the contribution of PCBs present in soil and concen-trations in human serum. This data set is considered relevant be-cause it closely examine PCBs in serum levels in a monitoredpopulation in close proximity to PCB-contaminated soils. Thesedata suggest that soil contaminated with PCBs contribute little ifany of these compounds to human body burden as measured byserum concentrations.

4.3. Alabama (US) case study

Orloff et al. (2003) evaluated the exposure of residents livingaround a plant that had produced PCBs in Anniston, Alabama. A totalof 18 families with young children who lived within a half-mile radiusof the plant participated in the study. Samples of soil, house dust, andblood were collected. The age range of the participants was 1–89 years with43 adults and 37 children. In children, the PCB blood lev-els ranged from non-detects to 4.6 ppb with a mean of 0.37 ppb. Inadults, the mean PCB concentration was 14.3 ppb and the median2.2 ppb. The much lower median value in the adult population is ex-plained by five outliers; the removal of the five outliers resulted in anadult mean PCB concentration of 3.5 ppb. The surface soil PCB concen-trations from the 19 homes ranged from non-detects to 11.7 ppm. Themean soilconcentration ofPCBs was 1.4 ppm (median: 0.6 ppm), withsoil samples collected from four residences containing PCB concentra-tions in excess of 1 ppm. A positive correlation was reported betweensoil and house dust PCB concentrations (rs = 0.628, p < 0.0052). A sig-nificant correlation between PCB soil and house dust concentrationsand serum concentrations could not be demonstrated, however, a sig-nificant correlation between PCB serum concentration and length ofresidence (duration unspecified) was reported (rs = 0.31, p < 0.0054;adjusted for age).

This case provides some evidence for judging the nature ormagnitude of the contribution of PCBs present in soil and concen-trations in human adipose tissue and serum. This data set is con-sidered relevant because it closely examine PCBs in serum levelsin a monitored population in close proximity to PCB-contaminatedsoils. These data suggest that soil contaminated with PCBs contrib-ute little of these compounds to human body burden as measuredby serum concentrations.

4.4. Michigan (US) case study

An extensive exposure study was reported by investigators ofthe University of Michigan (UM; University of Michigan School ofPublic Health, 2006; Garabrant et al., 2009). The details of thisstudy are described in the PCDD/F section (above). Jackson and Cal-houn Counties represented comparison areas with no knownindustrial sources of PCB contamination.

In blood samples, median individual PCB congeners rangedfrom 1.6 to 10,200 ppt in Floodplain, 1.6–11,700 ppt in Near Flood-plain, and 1.5–7020 ppt in Midland Plume. However, statisticalanalyses were not conducted to determine if any associationbetween blood levels and PCB soil concentrations were present

(Hedgeman et al., 2009). While demographic factors such as age,body mass index, sex, breast feeding, smoking explained much ofthe variance of PCB serum concentrations, diet, soil and householddust explained very little: 1% for PCB-126 and less than 0.01% forthe other congeners (University of Michigan School of PublicHealth, 2006).

Consequently, the UM case study provides support for judgingthe nature or magnitude of the contribution of PCBs present in soiland concentrations in human serum. The Michigan data set isconsidered relevant because it closely examines contaminatedsoils and serum levels in a carefully monitored population, and italso takes into account background levels of PCBs from a referencepopulation not residing on contaminated soils. Other potentialexposures and demographic factors were also evaluated Resultsof this study show that PCB-contaminated soil made little if anycontribution to human body burdens.

4.5. Toronto (Canada) case study

Yaffe and Reeder (1989) assessed human exposure at a site withPCB contamination in a Toronto community where the primarysource of potential exposure was soil. The geometric mean levelof PCBs in soil was 0.19 ppm. Children under 6 years of age wereconsidered at greatest risk because of their hand-to-mouth activi-ties. A sample of 30 children ages 1–5 from the contaminated areawas compared to 23 children of a control area with geometricmean PCB soil levels of 0.12 ppm. On a wet weight basis, the meanPCB blood levels of the study group with 1.5 ppb, and the controlswith 1.9 ppb were statistically similar. Levels in both groups ran-ged up to 5 ppb.

This case provides limited evidence for judging the nature ormagnitude of the contribution of PCBs present in soil and concen-trations in human serum. This data set is considered relevant be-cause they closely examine PCBs in serum levels in a monitoredpopulation in close proximity to PCB-contaminated soils. Thesedata suggest that soil contaminated with PCBs contributes little ifany of these compounds to human body burden as measured byserum concentrations.

4.6. Other US toxic waste site case studies

Stehr-Green et al. (1988) summarized results of earlier studiesin which PCB blood or adipose tissue levels were measured in peo-ple living in areas with high PCB soil levels usually around ‘‘toxicwaste sites”. In 10 of 12 site specific investigations, PCB serum lev-els of people considered to be exposed to PCB waste sites did notexceed those of a national or local reference population(<20 ppb). In these waste sites, PCB concentrations reached330,000 ppm in soil and 18 ppb in surface water leaching fromthe sites. At only two waste sites, where occupational exposureor consumption of contaminated fish occurred, was a proportionof serum PCB concentrations above that of the general populationat the 95th percentile (20 ppb) elevated.

These cases provide confirmatory evidence for judging the nat-ure or magnitude of the contribution of PCBs present in soil to con-centrations in human adipose tissue and serum. The data sets areconsidered relevant because they closely examine PCBs in serumlevels in a monitored population in close proximity to PCB-con-taminated soils. These data suggest that soil contaminated withPCBs contribute little if any of these compounds to human bodyburden as measured by serum concentrations.

4.7. Bioavailability

Uptake of PCBs and other chemicals is influenced by bioavail-ability. No studies of oral PCB bioavailability from actual soil at

50 R.D. Kimbrough et al. / Regulatory Toxicology and Pharmacology 57 (2010) 43–54

contaminated sites were available for review. Two studies usedspiked soils to determine oral absorption in rats. In one study, maleSprague–Dawley rats were given soil to which PCB congeners 118and 52 had been added in an ethanol solution (600 lg/kg bw) viaoral gavage. The ethanol was evaporated, and a water slurry wasprepared and shaken for 24 h prior to dosing the rats. Relative bio-availability ranged from 61.2% to 69.6% for PCB118 and 57.5–67.4%for PCB52, suggesting increased bioavailability for the higher chlo-rinated congeners (Pu et al., 2006). However, since this study didnot use weathered soil, it does not address the absorption of PCBcongeners from soil of contaminated sites. Similarly, the study byFries et al. (1989) did not directly address the question of absorp-tion from PCB contaminated sites. Fries et al. (1989) gave rats soilwith C14-labeled PCB congeners either by gavage or mixed into thediet. The soil had been stored in a freezer for eight years. Althoughradioactivity measured in feces of the rats does not distinguish be-tween absorbed and unabsorbed congeners, the authors assumedhigh bioavailability. The radioactivity in adipose tissue of the ratswas much lower. This study is difficult to interpret, and also doesnot add meaningfully to the question of bioavailability of PCBsfrom weathered soil, particularly since the freezing process (halt-ing chemical reactions) is incomparable to weathering which in-volves chemical transformations.

The human exposure data support the conclusion that humansare unlikely to increase their body burden of PCBs from soil. How-ever, the presently available animal data are limited as the studieswere not conducted using contaminated soil and, therefore, cannotproperly predict human absorption of PCBs from contaminatedsites. Contributing factors in support of this conclusion are the fre-quency with which people come into contact with the soil, the lackof uniformity of contamination, and the amounts of soil they comein contact with, which is quite small.

Overall, the evidence indicates consistently a lack of associationbetween PCB levels in residential soils or contaminated waste sitesand body burdens of PCBs in individuals who come in contact withPCB-contaminated soils.

5. Background levels of PCBs

The following provides an overview of background levels in theenvironment to put the above discussed cases into perspective.

Certainly PCBs are products of man-made chemical synthesis,yet minute amounts can also be formed in nature. Historically,PCBs were released to soil from application of sewage sludge, airdeposition of vehicular, incinerator or cement kiln emissions, acci-dental spills, industrial discharges or discharges from landfills.After the ban of PCB production in the US and severe restrictionson the recycling of PCB-containing materials, release of PCBs to soilgreatly diminished. Currently, accidental leaks or spills and re-leases from landfills or hazardous waste sites are the primarysources of PCBs in soil as deposition from vehicular or incineratoremissions are no longer important routes of exposure (ATSDR,2000).

In soil, PCBs are strongly adsorbed and very persistent, withhalf-lives ranging from months to years, depending on the positionof the chlorines and the degree of chlorination of different congen-ers (ATSDR, 2000; Gan and Berthouex, 1994; Kohl and Rice, 1998).However, highly chlorinated biphenyls are dechlorinated in aqua-tic sediments by microbial organisms (Bedard, 2001).

Although it is often stated that PCBs do not occur naturally inthe environment, they have been identified in low levels in allpre-industrial sediment subsamples from a remote lake in Finland(Isosaari et al., 2002). Their concentration ranged from 50 to2540 ng/kg dry weight, and the predominant congeners were 18,52, and 110. In archival soil collected from different locations

around the world in the early 1880s, Green et al. (2004) found totalPCBs ranging between 240 and 650 ng/kg dry weight. Concentra-tions increased in core sediment samples during their commercialuse. Similar observations were made in the northwestern part ofthe Baltic proper (Kjeller and Rappe, 1995). The commercial useof PCBs was mostly phased out worldwide during the later partof the 20th Century, and since then levels have been declining.

In the general population, diet is a major source of PCBs (IOM,2003). In an US FDA market-basket survey (1991–1997), meat, fish,and poultry were primary dietary sources of PCBs with fish being amajor contributing factor. PCB dietary intake in children (age6 months to 16 years) between 1991 and 1997 ranged from0.002 to 0.012 lg/kg-day, while PCB intake in adults (age 25–70 years) ranged from 0.003 to 0.005 lg/kg-day (ATSDR, 2000).

Huwe and Larsen (2005) investigated non-ortho PCB and PCDD/F levels in 65 meat samples collected from supermarkets across theUS in 2001. The TEQ for all samples was 0.55 ng/kg lipid with arange of non-detected to 3.21 ng/kg lipid. The estimated daily die-tary intake from meat products ranged from 5.3 to 16.0 pg TEQ li-pid (Huwe and Larsen, 2005). The contribution of PCBs to theoverall TEQ was low, ranging from 0.1 to 0.8 pg in beef fat, 0.02–0.2 pg in chicken fat and from non-detect to 0.02 pg in pork fat.These TEQ values are similar to those reported from other coun-tries (Huwe and Larsen, 2005). Recent studies and market-baseddata suggest that the intake of these chemicals in the US and inWestern Europe has declined over the past several decades, how-ever, data limitations prevent exact statistics (Aylward and Hays,2002; FDA, 2008; Pohl et al., 2007).

Inhalation of PCBs via ambient air contributes only a relativelysmall amount to the human body burden, and that contribution isdecreasing slowly over time. In remote areas such as Lake Maggi-ore in Italy and Switzerland, non-dioxin-like PCBs in air, includingparticulate matter, were measured at 80 pg/m3 (Vives et al., 2007).The mean atmospheric concentration in urban air in the US(�1990) has been reported to be 5 ng/m3 (Eisenreich et al., 1992;Kimbrough and Krouskas, 2003). PCB air levels were also measuredbetween 1990 and 2003 at six regional representative sites as partof the Integrated Atmospheric Deposition Network around theGreat Lakes (Sun et al., 2007). According to the authors, atmo-spheric PCB concentrations are decreasing with levels ranging from60 to 230 pg/m3. The highest concentration was observed at amonitoring site near Lake Erie, most likely due to urban activity.A correlation of gas phase PCB concentrations with local popula-tions indicates a strong urban source of PCBs. This finding is furthersupported by levels of 1300 pg/m3 found in Chicago (Sun et al.,2006).

Cleverly et al. (2007) measured the atmospheric concentrationsof PCDD/Fs and co-planar PCBs in rural and remote areas of the USbetween June 1998 and December 2002. In this study, levels, ex-pressed as TEQ values, were in the low femtogram/m3 range, indi-cating that the contribution of the co-planar PCBs via ambient air isnegligible.

PCBs are highly lipid soluble compounds; and because of theirextremely low water solubility, PCBs are present in drinking waterat very low concentrations (<1 lg/L), if at all, and are usually asso-ciated with point sources that may have contaminated water fromwells, rivers, and lakes. At such low concentrations, PCBs in drink-ing water are expected to provide little or no contribution to thehuman body burden (ATSDR, 2000).

A substantial downward trend in human body burdens of PCBshas also been observed since the commercial use of PCBs was cur-tailed many years ago (1977 in the US) (CDC, 2005; Kimbrough andKrouskas, 2003). PCBs have been identified in the environmentever since analytical methods were developed to measure them(Jensen, 1966). Because they are lipid soluble, PCBs are concen-trated in adipose tissue, but are also present in other tissues

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including blood. Concentrations in blood and in other tissues are inequilibrium on a lipid basis with adipose tissue, and thus should bequantified as such.

In the late 1980s and the early 1990s, median PCB serum levelson a wet weight basis ranged from 2 to 7 ppb. However, these val-ues were not based on a representative sampling of the populationof the United States (ATSDR, 2000). US CDC recently published itsthird National Report on Human Exposure to EnvironmentalChemicals, which contained 34 PCB congeners, and the congener-specific PCB serum data demonstrated strong age-related trends,with older individuals displaying higher concentrations of mostcongeners and of summed PCB congeners (CDC, 2005; Nicholset al., 2007). Differences between the youngest and the oldestgroups in the US CDC data set vary by at least a factor of eight.For the 12–39 year-old participants of this study particularly atthe 50th percentile, most lipid adjusted serum PCB levels were be-low the limit of detection of the analytical method (CDC, 2005). Ifthe limit of detection were assumed to equal zero, the calculatedsummed PCB levels might be 10 times lower in the 12–19 year oldsthan when half of the limit of detection was used for summing thecongeners. The sum of lipid adjusted PCB serum levels at 10 yearintervals over 8 decades ranged from 15 to 550 lg/L at the 50thpercentile when zero was used for the non-detectable levels andfrom 163 to 582 lg/L when half of the limit of detection was used.Differences are greater in the younger age groups since more mea-surements are now non-detectable. Nichols et al. (2007) concludedthat these age-specific reference ranges for PCBs are critical toaccurately interpret individual serum PCB concentrations. Levelsare higher in older adults in part because of a slower metabolismin the elderly and perhaps because of higher exposures in the past(CDC, 2005). Presently, in spite of lower limits of detection, manyyounger people no longer have detectable levels of PCBs in serum.

In the past, levels in human milk in various countries averagedaround 1 ppm on a lipid basis (Kimbrough and Krouskas, 2003) andhave shown decreases in recent years. According to ATSDR (2000),PCB levels in Swedish human milk decreased from 1.1 ppm lipid in1972 to 0.4 ppm lipid in 1992. In addition, PCB levels in Germanhuman milk decreased from 1.3 ppm lipid in 1986 to 0.45 ppm li-pid in 1996. Mean levels in Canadian human milk samples havealso decreased, and now range from 238 to 271 lg/kg lipid (ATSDR,2000).

6. Discussion and conclusions

Two groups of lipophilic and bioaccumulative compounds(PCDD/Fs and PCBs) are persistent in soils and, consequently, haveevoked concerns that they will be absorbed into the body of thosewho come into contact with that soil, particularly in residentialareas. An extensive and critical analysis of the literature surround-ing this hypothesis indicates that, except in extraordinary circum-stances, these chemicals do not make any meaningful contributionto body burdens in humans exposed to contaminated soils.

For PCDD/Fs, extensive studies of two major accidental dis-charges of these compounds (Missouri sites in the US and Seveso,Italy) have failed to correlate increases in human tissue concentra-tions with their levels in soils. This outcome is likely due in part tothe relatively tight binding of the chemical to the soil particles,sharply reducing their bioavailability for humans via ingestion,inhalation, and skin contact. The near absence of volatility pre-cludes vaporization and thus inhalation of the compounds them-selves; they may be taken up by some plants, but that is nottypical (ATSDR, 2000); and they are practically insoluble in water,virtually eliminating exposures via tap water. ‘‘Weathering” pro-duces tighter binding of chemicals to soil over time and the pres-ence of organic matter in the soil reduces absorption by the GItract. Furthermore, since in most cases contamination is not uni-

form, contact with contaminated soil does not occur on a frequent(e.g., daily) basis. Exposure is reduced even further because ofinclement weather conditions and natural barriers such as grass.Based on these experiences, levels of PCDD/Fs in soils as describedherein should not contribute to body burden.

Furthermore, humans, in general, do not appear to be intrinsi-cally sensitive to the effects of PCDD/Fs (Okey, 2007). Thus, clean-ing up PCDD/Fs-contaminated soil as a remedy to reduce humanrisk (as some have proposed), where soil and sediment are the onlypotential exposure pathways, would likely provide no tangiblehealth benefits. Although all of these compounds are present inthe environment, in the US the concentrations of PCDFs in humanbody fluids and tissues are proportionally lower than those ofPCDDs if they can be detected at all. PCDFs contribute very littleto body burdens, as demonstrated by their lower contribution toTEQs; with the 2005 TEF values, 14% contribution using NHANES2001–2002 data and 16.4% with the UMDES data (Hong et al.,2009). By contrast to the lack of impact of soil contact with thesecompounds, in the general population food is the major contribu-tor to human body burdens and some congeners are retained bythe body for long periods of time. However, when PCDFs werepresent in high concentrations in food from the contaminated oilas in the Yusho and Yucheng poisoning episodes (Kimbrough andKrouskas, 2003), they were retained in the body for long periodsof time.

The situation for PCBs is all the more compelling than that forPCDD/Fs, supporting the conclusion that their presence in residen-tial soils does not contribute to body burdens. Monitoring studiesof people living on soil contaminated with PCBs have shown nohigher body burdens than within the general population whenthe studies were controlled for confounders such as age, food,occupation, and other sources of exposure. No correlation betweenPCB levels in soil and human PCB blood could be demonstrated inthe many studies evaluated in this paper.

The University of Michigan study provided some unique per-spective in addressing both PCDD/Fs and PCBs. This study ad-dresses the possible role of age of exposure in estimating thehalf-life in serum, since four age groups (18–29 years, 30–44 years,45–59 years, and 60 + years) were included and the participantshad been in proximity of contaminated soils for extended dura-tions of time. The duration of this study would likely have capturedany lag in serum levels influenced by storage. The apparent half-life of these lipophilic substances in various age groups is the netresult of elimination rates, metabolic rates, and dilution relatedgrowth rates, which appear to be integrated in this study. Whilenot apparent in these data, the toxicokinetics of these highly fatsoluble substances would likely impact serum levels differentlyin children than in adults, in part, because the fat stores are quan-titatively different and the compounds are stored in fat.

Our analysis contains uncertainty from several sources. First,the selected data sets represent information that was obtainedfor reasons other than the objectives of our analysis. Consequently,the information provides limited opportunity for genuinely effec-tive comparisons. For instance, the Missouri case study involvesexposures to PCDD/Fs via an oil medium; and the contact withthese chemicals is limited to either occupational exposures or nar-rowly focused recreational activities (horse-back riding) whichmay lead to inhalation of contaminated dust, a situation not readilycomparable to that in a residential neighborhood. By contrast, theMichigan data set is quite applicable to the desired comparison be-cause the potential for exposures to these congeners is in a resi-dential setting and information about residence times and othersources of exposure (such as fish consumption) are reasonably welldocumented.

Another factor contributing to uncertainty in our analysis is therole of toxicokinetics of the congeners in the ability to detect small

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incremental additions to body burden of each study population.Milbrath et al. (2009) have reported on the approximate half-lifeof numerous PCDD/F and PCB congeners in children and adults.They found a linear relationship between half-life and age, bodyfat, smoking and breast feeding. With mean half-lives of specific di-oxin/furan congeners between 3 and 10 years, the detection ofsmall incremental increases in these congeners might require asubstantial addition to body burden from a single source (such assoil) even in the absence of dietary contributions to such burdens.However, if the overall body burdens were actually decreasing, theaddition of a small repeated dose from a single source (as in thecase in Michigan) would be expected to be detectable with currentanalytical methods given sufficient time between exposure andmeasurement.

Consideration of the body burden for these classes of com-pounds, for which lipid adjusted serum levels are representative,is important. Since body burden is likely to relate to the availabilityof the compound in reaching sensitive biochemical receptors. Rel-atively few studies report adipose tissue levels because of the tech-nical difficulties (biopsy) and ethical considerations in obtainingadipose tissue samples. Since an equilibrium in the concentrationsof these compounds exists between lipids in blood and adipose tis-sue (except for the brain) (Phillips et al., 1989), lipid adjusted ser-um levels are an acceptable surrogate for adipose tissuemeasurements.

The matter of gastrointestinal absorption has been the subjectof much debate. In the USEPA Superfund guidance documents,the default percent gastrointestinal absorption from oral ingestionof contaminated soil was estimated to be 50–70% for TCDD and>50% for PCDD/Fs (EPA, 2004). These defaults, while of practical va-lue years ago, can be supplanted by values based on increasedunderstanding of the bioavailability of these compounds underenvironmental conditions, such as binding to soil particles and sed-iments as is most often the case at contaminated sites. Applicationof this empirical knowledge leads to much lower estimates of gas-trointestinal absorption. Such information needs to be consideredproperly in evaluating the significance of exposure used in riskassessment for soil contamination scenarios. To do so would beconsistent with the realization that differing sources (includingsoil) contribute differently to exposure for PCDD/Fs and PCBs.

An interesting contrast exists between PCDD/F and PCBs andlead with regard to the contribution of each of these to body bur-dens in humans. Lead soil exposure has been studied extensively todetermine sources of exposures. Whether lead is easily absorbeddepends on the form of the lead (water solubility) and the particlesize; for the lipophilic compounds, neither of these properties ap-pears to be a major factor in absorption into the blood stream. Chil-dren under 6 years of age are prone to accumulate lead; whereasthat age group does not necessarily preferentially accumulatePCDD/Fs and PCBs. The primary vehicle for them is lead contami-nated house dust although other sources such as food, air, andwater also make a contribution to body burden; for PCDD/Fs andPCBs, the diet (particularly contaminated fish) is the primary con-tributor to body burden. Soil immediately around houses is a min-or source of lead when it is a source at all; similarly, soil appears tobe a minor contributor to body burden of PCDD/Fs and PCBs. Beforelead was removed from gasoline and lead air levels were higher, itwas difficult to determine what exactly the sources of lead werethat resulted in elevated blood lead levels. Since the removal oflead from gasoline and decreases in lead in food, overall blood leadlevels of the 1–6-year-old population have declined dramatically.However, in inner cities some children still have elevated bloodlead levels, even though overall those levels may be lower thanthey were in the past. In many instances old dilapidated houseswith peeling paint seem to be associated with such higher expo-sures (Kimbrough et al., 1995) while soil around the houses makes

a minor (�3%) contribution (Kimbrough et al., 1995; Weitzmannet al., 1993) to overall lead body burden. Studies conducted in Bal-timore and Cincinnati (US) to determine whether abatement oflead in soil would reduce blood lead concentrations in children alsoshowed no significant evidence of a reduction in blood lead levels(EPA, 1996). For PCDD/Fs and PCBs, decreases in serum levels weremore closely related to changes in dietary patterns, particularly de-creased consumption of contaminated fish.

In addition to urban areas, communities are contaminated withlead primarily in the mountains because of mining activities. How-ever, mine tailings are not a source of lead for young children or foradults living in towns with past or present mining activities. Theprimary reason may be the form of the lead and the fact that theparticle size of the tailings is larger than dust particles and is oftenmade up of pebbles. In the past when smelting also occurred andair emissions were poorly controlled (Hilts et al., 1998; Hilts,2003), children had elevated blood lead levels. Different exposurepathways were not sufficiently evaluated and soil contaminationwas also suspected as the culprit. However, more recent data (Hiltset al., 1998; Hilts, 2003) clearly demonstrates that mine tailingsand soil contamination from this source do not contribute to bloodlead levels in children or adults.

By comparison, the impact on serum levels of the lipid solubleorganics differs substantially from that of lead. Hence, lead is nota useful or desirable surrogate for PCDD/Fs and PCBs.

In conclusion, the contribution of soil contaminated with PCDD/Fs or PCBs to overall exposure of humans to these chemicalsappears to be negligible (61%). The setting of the low ‘‘CDC levelsof concern” for TCDD and of the regulatory clean up levels set forpersistent organic chemicals such as PCDD/Fs and PCBs by the USEPA and the states is predicated on the presumption that theirpresence in residential soil provides not only an opportunity forhuman exposures but also contributes meaningfully to their back-ground body burdens. The evidence provided herein indicates thatsuch a generic proposition is not supported.

If, as we believe, contact with soils contaminated with dioxins,furans, or PCBs will contribute no more than 1% (and probably con-siderably less) over the long term to the body burden, our findingsshould be considered as part of the overall body of evidence whenauthorities propose either to set levels of concern or to formulaterisk management approaches.

Acknowledgments

This paper is dedicated to the memory of Thomas F. Long. Thiswork was supported by The Dow Chemical Company. Thank youfor the encouragement provided by Ben Baker and Robert Budinskyof Dow Chemical Company.

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