Risk Assessment (ENST 830)

Mr. Mark Weisberg's Lectures from January 28 and February 2, 1999

January 28, 1999
Exposures, Into the Body, Toxicity and Toxic Risk

Exposures

Exposure Assessment: Determination or estimation (qualitative or quantitative) of the magnitude, frequency, duration, and route of exposure.

All chemicals are toxic under some conditions of exposure. Toxicity = Production of damage to the structure or functioning of any body part.

Definitions:

  • Absorbed Dose - crossing exchange boundary
  • Administered Dose - in contact with boundary
  • Applied Dose - dermal administered dose
  • Chronic Daily Intake - administered dose in mg/kg-days; > 7 years
  • Contact Rate - Amt. of medium contacted/time (2 L H2O/day; 100 mg soil/day; 1 mg soil/cm2)
  • Exposure Event - Contact incidence (per hour, per day, one-time event (acute)
  • Exposure Pathway - transport pathway from sources to exposed organism
  • Exposure Point - Location of potential contact in the environment
  • Exposure Route - Chemical entry into body (ingestion, inhalation, dermal contact, injection)
  • Intake - Measure of exposure (mg/kg-days)
  • Lifetime Daily Average Intake - exposure expressed in mg/kg-days over a lifetime (for carcinogenic endpoints)
  • Subchronic Daily Intake - administered dose in mg/kg-days; > 2 weeks and < 7 years

    Some examples of media exposure:

  • Ingestion and dermal contact with soil, and inhalation of mobilized soil particles
  • Ingestion and dermal contact with water, and inhalation of volatilized organics
  • Exposure to air-borne particulates can give rise to both inhalation exposure and ingestion exposure, when particles are collected in the mouth and swallowed

    Example of Dose Calculation

  • Aspirin tablet=325 mg, 4 tablets/day=1300 mg
  • Body weight of typical adult=145 lbs or 65 kg
  • 1300 mg/65 kg=20 mg/kg body wt. (bw)/day
  • For a child, the same 4 tablets/day = 1300 mg/20 kg = 65 mg/kg bw/day (more than 3 times the dose)
    Note: extrapolation of dose from animals to humans, using body weight or surface area normalization factor(s), must consider target organ of interest.

    • Typical EPA Exposure Assessment Includes:

    Step 1 - Characterize Exposure Setting

  • Physical Environment
  • Potentially Exposed Populations
  • Potential sensitive receptors

    Step 2 - Identify Exposure Pathways

  • Chemical Source
  • Release Mechanism
  • Exposure Point
  • Exposure Route

    Step 3 -

  • Quantify exposure by combining results from Exposure Setting (Step 1) and
  • Exposure Pathways (Step 2), using exposure concentrations and intake variables
  • Prepare summary tables for exposure assessment findings

    General Intake Equations (from RAGS)

    Intake Variables

  • Cw = Conc in H2O (mg/L)
  • Cs = Conc in Soil (mg/kg)
  • Ca = Conc in Air (mg/m3)
  • Cf = Conc in Food (mg/kg)
  • IR = Intake Rate, e.g.
    mL/day (sw, gw)
    mg/day (soil, food)
    m3/day (vapors, dust)
  • BW = Body Weight (kg)
  • SA = Skin Area (cm2)
  • PC = Perm. Constant (cm/hr)
  • AF = Adh. Factor (mg/cm2)
  • ABS = Absorb. Factor
  • ET = Exp. Time (hrs/day)
  • EF = Exp. Freq. (days/yr)
  • ED = Exp. Duration (yrs)
  • CF = Conversion Factors
  • FI = Fraction Ingested (food)

    Media Concentrations

  • Determine Distribution Type: Coefficient of Variation (COV) gives approximation; COV = Standard Deviation divided by the Mean; COV < 1: Normal Distribution; COV > 1: Log Normal Distribution (or undefined)
  • Depending on distribution, calculate 95% UCL using Supplemental Reading M-4 (Supplemental Guidance to RAGS: Calculating the Concentration Term [EPA, 1992])
  • Use 95% UCL or MDC, whichever is lower
  • Treatment of Nondetects: 1/2 DL used;Note: if elevated DL, delete if 1/2 DL > MDC
  • Detections of cmpds in lab blank: Common lab contaminants: use 10x rule; methylene chloride, acetone, toluene, 2-butanone, phthalates [including bis(2-ethylhexyl)phthalate]; All others: use 5x rule

    Supplemental Guidance to RAGS: Standard Default Exposure Factors (EPA, 1991) - Supplemental Reading M-8

    Soil Ingestion

  • Adult: 100 mg/day
  • Child: 200 mg/day
  • Worker: 50 mg/day
    Water Ingestion
  • Adult: 2 liters/day
  • Child: 1.4 liter/day
  • Worker: 1 liter/day
    Body Wt: 70 & 15 kg
    Inhalation Rate
  • Adult: 20 m3/day
  • Child: 15 m3/day
    Exposure Frequency
  • Residential: 350 days/yr
  • Comm/Ind: 250 days/yr
    Exposure Duration
  • Residential: 30 yrs
  • Comm/Ind: 25 yrs
    Important New Guidance: Exposure Factors Handbook (EPA, 1997)
  • Volume 1 - General Factors
  • Volume 2 - Food Ingestion Factors
  • Volume 3 - Activity Factors
    EPA, 1997, Office of Research and Development, Washington, D.C. EPA/600/P-95/002Fa, August
    Averaging Time (AT) (in days):
  • For noncarcinogenic endpoint, AT = ED, i.e., 30 years = 30 yrs x 365 days/yr = 10,950 days
  • For carcinogenic endpoint, AT = lifetime exposure = 70 yrs x 365 days/yr = 25,550 days
  • Remember, Intake expressed in mg/kg-days
  • Thus, carcinogenic intake different than noncarcinogenic intake (e.g., benzene)
  • Chemical intakes combined across viable exposure pathways, thus for child receptor, benzene intakes could come from: groundwater ingestion and shower contact; surface water ingestion and contact (swimming); incidental soil ingestion and dermal contact; soil and groundwater vapor inhalation; soil particulate inhalation (wind erosion); impacted food ingestion (vegetable uptake)

    Into the Body

  • Local toxicity = effect at point of contact
  • Systemic toxicity = absorbed (via skin, lungs, GI), with effect at distant target organ
  • ADME fundamental to understanding of potential toxic effects, including nature of toxic damage, where damage occurs in the body, severity of damage, and reversibility
  • ADME studies on animals, and extrapolated

    Absorption

  • Gastrointestinal Tract: Includes mouth, throat, esophagus, stomach, small and large intestine, rectum, and anus; Chemicals move through membrane of cells in the walls of GI tract (via absorption) into blood; Many factors affect rate of absorption, such as: chemical/physical properties of constituent; medium (food, H2O, soil); and host factors (age, nutritional status, general health, species)
  • Respiratory Tract: Includes nose, mouth, tracheae, lungs, bronchi and alveoli; Chemicals pass through the lungs (alveolar area) into the blood; Dust particles, particularly those < 2.5-10 microns in size, are deposited deep in the lungs; Asbestos: well studied inhalation toxic cmpd
  • Skin: Dermal (percutaneous) absorption = diffusion of chemical through the epidermis, including the outer stratum corneum layer and the underlying dermis layer, into the blood; Solvents are absorbed readily, lipophillic cmpds and large molecules are not; absorption estimated using dermal permeability constants (cm/hr) based on lab studies
    Distribution
  • In the blood, cmpd targets specific organs
  • Natural barriers that prevent or slow distribution include the blood-brain barrier and the placental barrier
  • Cmpds that can pass these two barriers are methyl mercury and alcohol, respectively
  • Cmpds also stored in adipose tissue or bone, and equilibrium is established
    Metabolism
  • Chemical changes occur in the liver, as well as in the skin, lungs, intestines, and kidneys
  • Chemical metabolites formed, which are usually more readily excreted from the body (detoxification pathway)
  • The more rapidly cmpd is metabolized and excreted, the less chance it may cause injury
  • Metabolism is catalyzed by protein enzymes
  • Some metabolites are more toxic than the parent compound, others less so: Toluene is metabolized in the liver to the less toxic compound benzoic acid; Bromobenzene is metabolized in the liver to the more toxic bromobenzene epoxide, although a threshold effect exists
  • Metabolism differences between species can be extreme, and may be the most important factor accounting for differences in response to chemical toxicity among animal species and individuals within a species
    Excretion
  • Chemicals and their metabolites excreted from body at different rates: minutes - years
  • Urinary excretion is the most common elimination pathway from the body

    Other elimination pathways: VOCs move from blood to lungs and are exhaled; cmpds partition into bile and feces

  • Minor pathways: sweat, saliva, semen, milk
    Fate and Transport
  • Leaching from soil to groundwater
  • Overland runoff to surface water
  • Groundwater discharge to SW or seeps
  • Groundwater transport
  • Wind mobilization of soil particles to ambient air
  • Uptake by crops from soil (pore water)
  • Volatilization from soil, groundwater, or surface water to ambient air
  • Volatilization from subsoil and groundwater to indoor air
  • Bioaccumulation in fish from surface water
  • Bioaccumulation in the terrestrial food chain (soil to plants to beef to humans)
  • Transfer to mother's milk
  • Soil Erosion (Particulate Emission Factor): PEF = 4.63 x 109 m3/kg (recommended default for wind erosion; bare soil [RAGS Part B]); site-specific factor may be calc'd using site area, wind speed, surface roughness, etc.; Thus, Ambient Air Concentration (mg/m3) = surface soil concentration mg/kg)PEF (m3/kg)
  • Indoor Volatilization Factor for Impacted Groundwater Household Use: VF = 0.5 L/m3 (recommended default value; based on TCE study [RAGS Part B])
  • Thus, Indoor Air Concentration (mg/m3) = Groundwater Conc. (mg/L) x VF (L/m3)

    Toxicity and Toxic Risk
    Toxicologists

    Paracelsus (1493-1541) Swiss physician, "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."

    Bernardino Ramazzini (1700), Italian physician and father of occupational medicine (Pb, Hg)

    Sir Percival Pott (1775) London physician published first record of occupational exposure (chimney sweeps and cancer of the scrotum)

    Claude Bernard (1813-1878) French physiologist, developed modern understanding of drug action and drug toxicity

    Alice Hamilton (1869-1970) Fort Wayne physician, work on mines and mills led to workers Worker's Compensation laws

    Harvey Wiley, chief chemist at USDA, whose work led to the Pure Food and Drug Act (1906)

    Philip Hawk (WW I era) pioneering work on vitamins and the development of experimental animal models for studying chemical effects

    Eugene Geiling, Univ. of Chicago, studied poisoning of 100 people from "Elixir of Sulfanilamide" (antibiotic prepared in diethylene glycol solution), led to Food, Drug, and Cosmetics Act of 1938

    Stafford Warren, Univ. of Rochester, developed approach to study the toxicology of inhaled (radioactive) substances during the Manhattan Project

    Rachel Carson 1962 publication of Silent Spring, studies pesticide toxicity, helped pave the way for major federal environmental laws of the 1960s and creation of the EPA in 1970

    Dr. Needleman, U. Pitt (1980s) - Pb effects

    Toxicity and Toxic Risk

  • All chemicals, natural and synthetic, are toxic (produce adverse health effects) under some conditions of exposure
  • Toxicologists study toxic effects on lab rodents using chronic studies of 2 years (equivalent lifetime exposure), subchronic studies of 90 days, and acute studies (single dose)
  • Delayed effects (chronic effects): effects that do not appear immediately after exposure, but after a delay (e.g., cancers)
  • Chronic effects may/may not require chronic exposure (acute benzene exposure)
  • Carcinogens: class of chemicals capable of producing excess tumors throughout the body
  • Teratogens: chemicals capable of causing birth defects (from the Greek "teras" meaning "monster."
  • Some toxic effects are reversible (limited ingestion of alcohol = hangover) while others are nonreversible (chronic ingestion of excess alcohol = cirrhosis of the liver)
  • Risk: the likelihood, or probability, that the toxic properties of a chemical will be produced in populations of individuals under their actual conditions of exposure
  • To evaluate the risk of chemical toxicity, at least 3 types of information are needed: (1) The types of toxicity the chemical can produce (targets and forms of injury); (2) Conditions of exposure (dose and duration) under which the chemical's toxicity occurs; (3) The conditions (dose, timing, and duration) under which populations may be exposed

    February 2, 1999
    Fast Poisons, Slow Poisons, and Carcinogenicity

    Fast Poisons

  • Acute toxicity = Fast Poison
  • Botulism toxins, one of the most acutely toxic of all poisons - lethal at single acute dose of 0.00001 (1 x 10-5) mg/kg b.w.
  • Sugar is also acutely toxic, at single dose of 20,000 (1 x 104) mg/kg b.w. or about 3 lbs. for a human
  • These two differ in toxicity by factor of 109
    Important to note that some chemicals that are toxic at some elevated acute dose, are not toxic at all at a lower subchronic dose
  • Natural sources of acute toxic chemicals: plants (tobacco, water hemlock, Jimson weed, foxglove, poison ivy, poison oak, potatoes); bacteria (Botulism toxin, salmonella); spiders (black widow, brown recluse); fish (puffer, stingray, bullheads);invertebrates (jellyfish); shellfish (red tide - paralytic shellfish poison - dinoflagellate algae); reptiles (rattle snake, cobra, coral snake); amphibians (e.g., poison dart frog)
  • Some acute toxins affect some species more than others: Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,3,7,8-TCDD) is toxic to female guinea pigs at a single dose of 0.0006 mg/kg b.w., but is 5,000 times less toxic to hamsters; (Dioxin is also a suspected human carcinogen)
  • The types and severity of effects vary, characterized by a chemical specific dose-response relationship.
  • Toxic properties are identified in 3 ways: (1) Case Reports (least scientific); (2) Epidemiological Approaches; 3) Laboratory Studies (most scientific)
  • Case Reports: Reports, typically from physicians, detailing adverse health effects from chemical exposure; May include accidental poisonings, drug overdoses, homicide or suicide attempts; Case reports are not controlled scientific studies; Good for ID of immediate and easily characterized effects, but generally only provide clues to environmental chemical risks
  • Epidemiological Approaches: Retrospective (backward looking) or prospective (cohort - forward looking) studies of how diseases are distributed in the populations, using statistical analysis; Difficult to prove cause-effect relationship (e.g., cigarette smoking and lung cancer); Many confounding variables
  • Laboratory Studies: Toxicity tests or bioassays - study in which chemicals are administered to groups of animals (typically by gavage) and observations are made on adverse effects, if any; Mechanism of toxic action studies - study in which whole or part of animal is used (cell line) to obtain information on ADME; Toxicity studies can be controlled, i.e., use of test group and control, where the only difference is chemical dose (e.g., 0, 20 mg/kg); Can obtain data on all the target organs that may be adversely affected (animal sacrificed at end of study and pathology studies completed); Results = LD50 (50% of test group affected)

    Slow Poisons

  • Endpoint of concern for slow poisons (via chronic or subchronic lab tests) is the NOAEL (NOEL)
  • NOAEL = No-observed adverse effect level or the max dose at which the chemical produces no observable toxicity
  • Remember: for Fast Poisons, the endpoint of concern was acute toxicity (LD50)

    Toxicity Testing

  • Route of Administration: Match the route of exposure in the test (i.e., ingestion, inhalation, dermal contact) to the most likely routes of human exposure
  • Test Species: Select species most representative of humans for the chemical (typically rats, mice, rabbits); Know the species' life history and spontaneous disease occurrence
  • Controls: Use control group with spp of same sex, age, and state of health (animals selected randomly)
  • Number of Test Subjects: Most toxicity tests use 20 - 50 animals of each sex in each dose group (plus control); With sample size of 50/group, only effect differences of 5-10% can be statistically shown; Because the number of animals assigned to tox. tests groups largely determined by practical considerations*, the interpretations of results must consider limitations of small sample size; * $400,000 per species for chronic feeding study, and two species usually required; Non-significant findings are not ignored; i.e., rare brain lesion (< 5% incidence), although not statistically significant, would still be noted.
  • Dose Selection: Range of doses selected to produce dose-response relationship: rate of toxic response in test animals as a function of administered dose; Max. dose should not produce acute toxicity and min. dose should be NOAEL; Dichotomous response = yes/no effect: Continuous response = all individuals affected, but at varying degrees
  • Duration: Subchronic rodent test = 90 days (10% of lifetime), also used to help plan chronic study; Chronic test - 2 years (used to detect carcinogenic endpoints, if any)
  • Observations to be Made (include, but not limited to): Survival pattern; body wt.; food consumption rates; behavior; and blood and urine chemistry; After the study, animals are sacrificed, and examined by a pathologist; about 30 different tissues and organs are examined in histopathological examination
  • Tests follows "Good Laboratory Practices" : Careful control and monitoring required; Results submitted to federal government
  • Study Evaluations: All results listed, including both endpoints of biological significance and statistical significance (for test groups and control); Statistical significance typically defined as the P0.05, or 95% confidence limit (less than 1/20 probability that outcome due to chance alone); NOAEL vs NOEL (toxicologist reports both)

    Targets in the Body and Responses

  • Respiratory System: Irritation: (NH3; Cl2; SO2; CH2O [formaldehyde]); Dyspnea: feeling not being able to catch breath; Edema: swelling in the airway; Emphysema: cellular damage that results in loss of lung volume (O3; NO2); Fibrosis: lung scarring (SiO2; asbestos); Allergy: antigens/antibodies (toluene diisocyanate)
  • Gastrointestinal Tract: Cell damage (caustics, e.g., lye); Abdominal pain, vomiting and diarrhea (heavy metals such as Pb, Cd, As); Changes in adsorption (many chemicals)
  • Skin: Reddening, swelling, itching (many chemicals); Skin cancer (UV from sun; arsenic [As])
  • Blood: Interference with O2 carrying capacity of hemoglobin in RBCs, resulting in anoxia and toxicity (CO; NO2-1[nitrites]); Bone marrow damage and resulting RBC anemia (benzene; arsenic; TNT; gold; certain drugs; and ionizing radiation)
  • Lymphatic System (lymph glands & body's immune system): Immunosuppression and reduced resistance to infection and certain diseases such as cancer (also called immunotoxicity) (benzene; PCBs); Allergic response (toluene diisocyanate; nickel)
  • Liver (prime toxicity target: all ingested chemicals are carried to liver); Necrosis-cellular death (CCl4; CHCl3 chloroform); Cholestasis or decreased secretions of bile, leading to jaundice (therapeutic agents); Cirrhosis or scarring (CCl4; alcohol; aflatoxin)
  • Kidney (blood filtering mechanism): Tubule damage (heavy metals such as Hg; Cd; Cr; Pb, and excessive amounts of antibiotics); Cellular death (CCl4; CHCl3)
  • Nervous System: Demylination, or loss of myelin, a sheath for the neuron axon and dendrites (Pb; hexachlorophene; the drug isoniazid); Brain anoxia and cell death (CO; barbiturates); Peripheral neuropathies or damage to axonal neuron segments (carbon disulfide; metabolite of hexane; acrylamide, alcohol abuse); Neurotransmitter interruption (botulism, DDT); Neurotoxicity (Mn; MSG; Au species; metallic Hg, - "Mad Hatter disease" from Hg exposure by hat makers; methyl-Hg-"Minamata disease" from uptake of Hg by fish and shellfish, followed by ingestion by Japanese fishermen); Encephalopathy or brain disease and numerous behavioral effects (Pb exposure)
  • Reproductive System: Decrease in sperm count (pesticide DBCP; Cd); Other chemicals effect the fertility index (% of successful matings that result in pregnancy), gestation index (% of pregnancies resulting in live births), and viability index (% of offspring that survive > 4 days); Other chemicals effect the embryo or fetus (developmental toxicity) (thalidomide); Thalidomide, a sedative, was widely used to reduce nausea and vomiting during pregnancy: It was later found to be a powerful teratogen, causing birth defects with an absence of limbs and reduced limb length; Thalidomide's toxic effect was restricted to women taking the drug during the 6th and 7th week of pregnancy (a period of organogenesis in which the fetus' skeleton is under most rapid development); It should be noted that teratogens have been around for millennia, and predate the production of synthetic chemicals; Natural animal teratogens include certain range weeds, and the withholding of riboflavin or Vitamin A from the diet

    Carcinogens

  • Carcinogenic endpoints very common in humans (chance of about 1 in 5 of developing some form of cancer in lifetime)
  • Cancer: term that covers large group of diseases that affect humans, animals (>100)
  • Characterized by abnormal, unrestricted cell growth, with resulting mass compressing, invading, and destroying normal tissue.
  • Rapid cell growth also occurs normally, during injured tissue repair and healing, and during pregnancy, but is self-limiting
  • First cancer discovered about 1775 by Percival Pott (London chimney sweeps and scrotum cancer, linked to PAHs)
  • International Agency for Research on Cancer (IARC), part of WHO, categorizes chemicals based on the nature and extent of available scientific evidence on car-cinogenic activity; evidence is labeled as: Sufficient; Limited, or; Inadequate
  • IARC lists approximately 40 chemicals as carcinogenic to humans, and another two dozen or so as having limited evidence of human carcinogenicity
  • There are many natural carcinogens in the environment. 1981 study estimated only 5 - 8% of U.S. cancer deaths due to industrial chemicals present in the workplace (old data)
  • Carcinogens can be ID'd using epidemio-logical methods, but this results in retrospective information (after the fact)
  • Cancer clusters (hot spots) in the population ID'd, e.g., high rates of lung cancer in coastal areas of Georgia (later linked to asbestos used in ship building)
  • Case-reports also used

    Analytical epidemiological studies

  • Case control study: People with specific type of cancer identified and asked questions on types of exposures they may have experienced; Drawbacks: past exposures based on memory; Case-control results expressed as odds ratio (OR) (cases vs. controls)
  • Cohort study: Group of individuals (cohort) known to be exposed to suspect agent, compared with control group; Control group selected to be as similar as possible to cohort (age, sex, race, location, smoking habits, etc.); Results are expressed as Relative Risk (RR) (cohort vs. control); Cohort studies can be retrospective or prospective
  • Confounders: Other factors may be responsible for cancer, such as smoking, and if smoking rate is higher in cohort than control, smoking is a confounding variable
  • Causality: Results of epidemiological study cannot show strict cause-effect relationship, only causality

    Operational Definition of a Chemical Carcinogen

  • Ability to produce neoplasms in animal bioassay. Four types of response accepted as evidence of neoplasm induction: (1) presence of tumors types not seen in control; (2) increase in incidence of tumor types occurring compared to controls; (3) development of tumors earlier than in the control; (4) increase of tumor multiplicity (growth rate)
    Note: for evidence of carcinogenicity, production of even benign neoplasms is accepted, as no chemical has yet been identified that produces exclusively benign neoplasms: Regulatory agencies, as well as IARC, accept the above note, as cancer development is a multistage process, and benign neoplasms represent only the first stage of the process

    Animal Bioassays

  • Current bioassay protocol - four test groups: First group receives maximum tolerated dose (MTD); second group receives 1/2 MTD; third group receives 1/4 MTD; fourth group receives no dose (i.e., is the control group); Approx. 60 males and 60 females per test group; Study duration is 2 years (equivalent lifetime); For each animal, > 30 tissues and organs examined (= 40,000 individual slide readings)
  • All known human carcinogens (IARC's classification) have been shown to be capable of inducing cancers in some, but not all, species of experimental animals (except arsenic)
  • Examples:
    Aflatoxins
    4-Aminobiphenyl
    Asbestos (inhaled)
    Benzidine
    DES
    2-Naphthylamine
    Vinyl chloride
  • Weight of evidence approach for classification that chemical is human carcinogen should be used: Certain sites of tumor formation in some spp. and sexes of test animals are suspected of being uniquely susceptible to carcinogens, such that excesses are of minor human relevance; e.g., kidney of male rat undergoes degenerative changes as rat ages, and kidney becomes susceptible to certain types of tumors; Certain chemicals (gasoline and other hydrocarbons) are capable of accelerating the rate of kidney degeneration, and also increasing the rate of tumor production in male rates; Female rats, and other species are not affected; Thus, weight of evidence approach would suggest that chemicals that produce only male rate kidney tumors are not necessarily human carcinogens
  • Drawbacks with using the MTD approach: If MTD overshoots target dose and a negative outcome is observed, results may have been biased due to excess number of early deaths; If MTD undershoots target dose and a negative outcome is observed, results may not be convincing because dose was too low; If MTD overshoots target dose and positive outcome is observed, results may be suspect due to the fact that tumors may result from excess toxicity, and not carcinogenic potential; Cells are so damaged by toxicity of MTD that they may have been put at an extra high risk of progressing to the neoplastic state; A possible example is the link between excess bladder tumors seen in rats and stone deposition, when rats are subjected to the MTD; Application of the results of MTD lab tests to humans is problematic because humans are exposed at low doses, where the metabolic profile of the chemical can be vastly different
  • In conclusion, use of animal bioassays to predict whether chemicals are human carcinogens is controversial and an inexact science, but is one of the few tools we have.