Chapter 7:  Evaluation of Chemical Toxicity
Fundamental Concepts and Principles in Toxicology
*Studies conducted to determine several fate and behavior attributes of the chemical
**how easily the chemical enters the organism
**how the chemical behaves in the organism
**how rapidly the chemical is removed from the organism
**what cells are affected by the chemical
**what cell functions are impaired as a consequence of the chemical exposure
*Toxicity tends to vary according to…
**duration of receptor exposure
**location of receptor exposure
**receptor-specific responses of the exposed organisms
*indicates the state of adverse effects or symptoms being produced by toxicants in an organism
Mechanisms of toxicity
*toxicants exert their effect when they interact with cells
*general idea
**chemical substance is absorbed
**binding occurs with organs
**partitioning behavior between chemicals and different biomolecules of the body
*concepts relating to the mechanisms of toxicity for most toxic substances consider the following
**routes of chemical exposure and absorption
**distribution of the toxic chemical through the body
**biochemical transformation of the compound
**toxicant-receptor interaction
**storage of chemical
**excretion of chemical
*will vary with location of contact
Non-carcinogens
*operate by a “threshold” mechanism
**manifestation of effects requires a threshold level of exposure or dose to be exceeded during a continuous exposure episode
***protective mechanisms must be overcome
Carcinogens
*”non-threshold” mechanism
**essentially no level of exposure to such a chemical that does not pose a finite probability of causing a carcinogenic response
Mechanisms of carcinogenicity
*initiators–initiate carcinogenesis
*promotors–increases cancer induction after exposure to an initiator
**co-carcinogen–promotor administered at the same time as the initiator
*complete carcinogens–function as initiators and promotors
Processes of carcinogenicity
*initiation–genetic damage occurs through a mutation to DNA. This involves a change in the capacity of DNA to function properly.
*Promotion–genetic damage is expressed through the multiplication of cells in which initiation occurred previously
*progression–represents the spreading of cancer through uncontrolled cell growth
Identification of carcinogens
*epidemiological studies
**must consider latency period
**most commonly used study is long-term animal studies (not always representative of human response)
Manifestations of toxicity
*severity–increases as dose increases
*incidence–increases as dose increases (probabilistic)
*reversibility–symptoms disappear as exposure decreases
*irreversibility–toxic effects cannot be repaired
*seriousness–definite threats vs. non-obvious threats
Dose-response relationships
*most fundamental relationship in toxicology
*establishing a dose-response relationship
**the observed response is caused by the substance administered to the organisms
**the magnitude of the response is directly related to the magnitude of the dose
**it is possible to correctly observe and measure a response
Carcinogenic classification system
*carcinogenicity evaluation philosophies
**weight-of-evidence–consider and balance the negative indicators of carcinogenicity with those showing carcinogenic activity
**strength-of-evidence–consider combined strengths of all positive animal tests to rank a chemical without evaluating negative studies, nor considering potency or mechanism
Weight-of-evidence
*EPA classification system
**A–human carcinogen
**probable human carcinogen
***B1–limited human data
***B2–sufficient data in animals and inadequate or no evidence in humans
**C–possible human carcionogen
**not classified as to human carcinogenicity
**E–no evidence of carcinogenicity in humans
Strength-of-evidence
*International Agency for Research on Cancer (IARC)
**1–human carcinogen
**2–probable or possible human carcinogen
***2A–limited human evidence
***2B–sufficient evidence in animals and inadequate or no evidence in humans
**3–not classifiable as to human carcinogenicity
**4–no evidence of carcinogenicity in humans
Evaluation of chemical toxicity
*general methods of chemical toxicity assessment
**case clusters
**structural toxicology
**laboratory study of simple test systems
**long-term animal bioassays
**human studies
Hazard effects assessment
*used to determine whether exposure to an agent can cause an increase in the incidence of an adverse health effect
**characterization of the nature and strength of the evidence of causation
**process involves gathering and evaluating data on the types of health injury that may be produced by a chemical
*overall purpose is to review and evaluate data pertinent to answering questions relating to two key issues
**whether an agent may pose a hazard to potential receptors
**under what circumstances an identified hazard may be manifested
Assessment of toxicity of a chemical
*laboratory animal studies
*clinical case studies in humans
*epidemiological studies
Dose-response assessment and quantification
*response of a given toxicant depends on the mechanism of its action
*simplest scenario
R=k * [C]
**R=response
**k=rate
**C=concentration
*cumulative effect related to body burden
BB = ABS + STR – ELM – BTF
**BB = body burden
**ABS = rate of absorption
**STR = rate of storage
**ELM = rate of elimination
**BTF = rate of biotransformation
Nature of dose-response extrapolation models
*three major classes of mathematical extrapolation models for relating dose and response in sub-experimental dose ranges
**tolerance distribution models (i.e. Weibull)
**mechanistic models (i.e. one-hit)
**time-to-occurrence models (i.e. lognormal)
***used to extrapolate from non-threshold effects associated with carcinogenic responses that are observed at high doses to responses at low doses
Determination of toxicological parameters for human health risk
*non-carcinogenic parameter–RfD
**the maximum amount of a chemical that the human body can absorb without experiencing any chronic health effects
*RfC–represents an estimate of the exposure that can occur on a daily basis over a prolonged period with a reasonable anticipation that no adverse effect will occur
Derivation of RfD and RfC
*RfD = NOAEL (or LOAEL) / (UF * MF)
*RfC is a parallel process that uses a NOAEC or LOAEC
*Uncertainty factors (UF, factors of 10)–used to offset the uncertainties associated with extrapolations from available data
*modifying factor (MF)–between 0-10, qualitative professional assessment of scientific uncertainties in the study
Inter-conversions of non-carcinogenic toxicity parameters
*inhalation pathways
RfD = RfC * average human inhalation rate (20 m3/day) / BW (70 kg)
*drinking water equivalent level
DWEL = Oral RfD * BW / Ingestion rate
Making risk management decisions
*useful to risk managers
**margin of exposure (MOE)–magnitude by which the NOAEL of the critical toxic effects exceeds the estimated exposure dose (EED)
MOE = NOAEL / EDD
Toxicity parameters for carcinogenic effects
*two specific toxicity parameters
**cancer slope factor (CSF)–expresses the slope of the dose-response function
***measure of the carcinogenic toxicity or potency of a chemical (oral and dermal)
***plausible upper bound estimate of the probability of a response per unit intake of a chemical over a lifetime represented by the cancer risk per unit dose
**unit risk factor (URF)–expresses the slope in concentration-based units
***inhalation exposures
Derivations of SFs and URFs
*linearized multistage model
**most popular method amongst regulatory agencies
***conservative attributes
**model uses animal tumor incidence data to compute maximum likelihood estimates (MLE) an upper 95% confidence limit (UCL95)of risk associated with a particular dose
Inter-conversion of carcinogenic toxicity parameters
*SF can be converted to URF by adopting several assumptions
**endpoint is a systematic tumor–this assumes the same blood concentration to the target organ regardless of the method of administration
***implies equivalent absorption
***at low doses, the response curve is linear
Surrogate toxicity parameters
*we should consider every likely route of exposure in the evaluation process
*extrapolations are possible for some cases where there is reliable information on the degree of absorption of materials by both routes of exposure
**this assumes that the substance is not locally more active by one route over the other
Route-to-route extrapolation
*can be done, however…
**this introduces additional uncertainty into the overall process of risk assessment
**if you use PBPK models then you can reduce this uncertainty
Toxicity equivalency factors
*used to derive quantitative dose-response estimates for substances that are members of a certain category or class of agents
*assumptions:
**individual compounds act through the same biologic or toxic pathway
**effects in a mixture are additive
**dose-response curves for different congeners are parallel
**organotropic manifestations of all congeners must be identical over the relevant range of doses
Relative potency factors
*similar to TEF approach
*uses estimated order of potential potency relative to benchmark compound
*Example PAHs
**benchmark is BAP
Mechanisms of action and determination of human health effects
*mechanism of action–the complete sequence of biological events that must occur to produce an adverse effect
*mode of action–describes only major (but not all) biological events that are judged to be sufficient to inform about the shape of the dose-response curves beyond the range of observation
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