Environmental Health II. Toxicology

Shu-Chi Chang, Ph.D., P.E., P.A.Assistant Professor1 and Division Chief2

1Department of Environmental Engineering2Division of Occupational Safety and Health,

Center for Environmental Protection and Occupational Safety and Health

National Chung Hsing University

Outline

Short history Toxicology

Source of information Pathways of exposure and excretion Conventional tests Multiple chemical sensitivity Endpoints of toxicological evaluations Molecular toxicology Exploration of animal data Establishing exposure limit Applying toxicological data to the

environment

Short history about EH

“Silent spring” by Rachel Carson in 1962 Major effects

Awareness of the destruction of indiscriminate use of chemicals

Environmental laws were made in 1970’s “Our Stolen Future” Are We Threatening

our Fertility, Intelligence, and Survival? - by Dianne Dumanoski, et al. in 1997 Major effects

Awareness of the endocrine disruption caused by chemicals

Inspired the research on Green Chemistry and Environmental Hormones

Toxicology

Chemical usage 70,000 in common use and adding

200~1,000 annually Information is very limited especially

when exposed to numerous different chemicals

Toxicology is both a science and an art. Data gathering and projection

Source of information

Epidemiological studies (next session)

An array of lab studies In the past, toxic agents on animals

as complete organisms Now, exploring the responses and

effects of chemicals at the molecular level.

Pathways of exposure and excretion (1)

Major routes Inhalation Ingestion Absorption

Type Gaseous Particulate

Nature and intensity of chemicals’ effects Concentration Form Target organ How long (half-life)

Pathways of exposure and excretion (2)

Absorbed chemicals Biological transformation Bioactivation

Principal means of excretion Urine Liver lungs Sweat glands (less important) Note that GI is not a major route

Pathways of exposure and excretion (3)

Effects Reversible and irreversible Could be acute or delayed: carcinogenesis Allergic reactions Other factors: species and strains, age, sex,

and nutritional and hormone status. Physical factors: temperature, humidity,

light cycles Social factors

Pathways of exposure and excretion (4)

Pathways of exposure and excretion (5)

Pathways of exposure and excretion (5)

Biological accumulation and magnification

Conventional tests for toxicity

Acute toxicity studies A single or several administration of

the chemical within 24 hours Chronic toxicity studies

Short-term toxicity studies Repeated administrations, 10% life span 14-day and 28-day durations have been

used Long-term toxicity studies

Repeated administrations, entire life span

Acute toxicity studies

Gaussian distribution

Acute toxicity studies

Cumulative percentage

Which one is more toxic?

Acute toxicity studies

LD50: Lethal dose for half of the exposed population within a certain period of time.

Synergistic and antagonistic effects

Short-term and long-term tests

Short-term For more realistic situation Usually two or more species Most often rats and dogs Three levels of doses

Long-term “Acceptable intake”, “ no observed adverse effect

level” Body weight, body size, food consumption Lab tests: hematological tests Postmortem examination: histological examinations,

may measure the size of different organs.

Outcomes

Typical Target organs Effects Dose-effect and dose-response relationships Maximum tolerated dose Some may not be observed

Reproduction Disease Decreased longevity

Multiple chemical sensitivity

Trace concentrations of a combination of chemicals Difficult to confirm

Symptoms are usually subjective Exposure levels are orders of magnitude lower Symptoms appeared to have no relationship to known effects

Observations in the past No observable adverse effect One or only a few target organs No difference in the nature of response

Now for multiple chemical sensitivity No apparent safe level Multiple organ systems Individual difference in responses

US Agency for Toxic Substances and Disease Registry (ATSDR) developed “Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures”

Endpoints of Toxicological Evaluations

Carcinogenesis Initiator and promoter Activation of mutation of oncogenes or the

inactivation of suppressor genes Ames test

Reproductive toxicity Developmental toxicity

Embryo, fetal death, growth retardation, malformation

Thalidomide case Neurotoxicity

Cognitive, sensory, motor impairment Immunotoxicity

Suppress the immune function: AIDS Chemical AIDS

Thalidomide tragedy 1957 to 1962 in UK, Canada, Germany, Japan USA is not affected because FDA did not approve its

usage Prevented morning sickness 12,000 babies who survived, with phocomelia (flipper-

like arms or legs)

Molecular toxicity

Need to understand the fundamental mechanisms

Endpoints = Marker or indicators that signal the interaction in biological systems.

Three types of markers Are a measure of response or dose Signal effects Are indicative of susceptibility

Biomarkers enabled the use of DNA array for toxicological studies.

Extrapolation of animal data

Two kinds Extrapolation from small animals to human From much higher dose within shorter time

to much lower dose for long-term exposure Linear relationship (common

assumption) May not be appropriate for dioxin, thyroid-

type carcinogens, nitrolotriacetic acid, etc.

Dose response curve

Establishment of exposure limits (I)

Two principles Use of human data whenever possible Use of surrogate chemicals or surrogate

species only when scientific data showed evidence

Steps1. Identification of all adverse effects2. Establishment of dose-response relationship3. Establishment of chemical database4. Decision of the data relevance5. Use the data to establish exposure limit for

human

Establishment of exposure limits (II)

Safety factor X1/10: valid chronic exposure data

existed on human and supportive chronic data were available on other species

X1/100: no data on human but satisfactory chronic data existed for one or more other species

X1/1000: chronic toxicity data were limited

Applying toxicological data to the environment

Complications Different species or different groups of the

same species may have different effects Some populations may occur in more than

one form Synergistic and antagonistic Indirect effects may be greater that direct

ones Nonlethal chemicals may have

considerable ecological impact. Species other than human?

General Outlook

Most carcinogens found by epidemiological studies or by physicians

Cellular and molecular approaches Earthworms instead of rats and dogs

Data and resources SARA ATSDR and USEPA

National Priority List Pocket guide to chemical hazards Database

Carcinogenicity (<20%), epidemiology (<10%), teratogenesis (<10%)

Be aware of natural toxic chemicals