Term
Fundamental Concepts and Principles in Toxicology |
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Definition
*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 |
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Term
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Definition
*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 |
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Term
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Definition
*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 |
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Definition
*"non-threshold" mechanism **essentially no level of exposure to such a chemical that does not pose a finite probability of causing a carcinogenic response |
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Term
Mechanisms of carcinogenicity |
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Definition
*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 |
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Term
Processes of carcinogenicity |
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Definition
*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 |
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Term
Identification of carcinogens |
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Definition
*epidemiological studies **must consider latency period **most commonly used study is long-term animal studies (not always representative of human response) |
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Term
Manifestations of toxicity |
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Definition
*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 |
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Term
Dose-response relationships |
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Definition
*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 |
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Term
Carcinogenic classification system |
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Definition
*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 |
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Term
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Definition
*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 |
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Definition
*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 |
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Term
Evaluation of chemical toxicity |
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Definition
*general methods of chemical toxicity assessment **case clusters **structural toxicology **laboratory study of simple test systems **long-term animal bioassays **human studies |
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Term
Hazard effects assessment |
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Definition
*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 |
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Term
Assessment of toxicity of a chemical |
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Definition
*laboratory animal studies *clinical case studies in humans *epidemiological studies |
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Term
Dose-response assessment and quantification |
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Definition
*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 |
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Term
Nature of dose-response extrapolation models |
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Definition
*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 |
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Term
Determination of toxicological parameters for human health risk |
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Definition
*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 |
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Term
Derivation of RfD and RfC |
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Definition
*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 |
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Term
Inter-conversions of non-carcinogenic toxicity parameters |
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Definition
*inhalation pathways RfD = RfC * average human inhalation rate (20 m3/day) / BW (70 kg) *drinking water equivalent level DWEL = Oral RfD * BW / Ingestion rate |
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Term
Making risk management decisions |
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Definition
*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 |
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Term
Toxicity parameters for carcinogenic effects |
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Definition
*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 |
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Term
Derivations of SFs and URFs |
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Definition
*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 |
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Term
Inter-conversion of carcinogenic toxicity parameters |
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Definition
*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 |
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Term
Surrogate toxicity parameters |
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Definition
*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 |
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Term
Route-to-route extrapolation |
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Definition
*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 |
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Term
Toxicity equivalency factors |
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Definition
*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 |
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Term
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Definition
*similar to TEF approach *uses estimated order of potential potency relative to benchmark compound *Example PAHs **benchmark is BAP |
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Term
Mechanisms of action and determination of human health effects |
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Definition
*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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