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Dose Response and Descriptors. Dose-response assessment. Quantifying relationships between exposures and health effects: Dose-response relationship Dose-effect relationship Public health impact “Burden of disease and injury”. Dose-response curves for effects of lead in children.

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Dose Response and Descriptors

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Dose response and descriptors l.jpg

Dose Response and Descriptors


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Dose-response assessment

  • Quantifying relationships between exposures and health effects:

  • Dose-response relationship

  • Dose-effect relationship

  • Public health impact

  • “Burden of disease and injury”


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Dose-responsecurves for effects of lead in children


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Dose-Effect Relationship


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Dose Response

  • -Non-cancer effects

  • Cancer effects

  • Quantitative evaluation of hazard information

  • Characterization of the relationship between hazardous agent and incidence of adverse health effect

  • This relationship yields hazard values (Reference dose and Slope factor)

  • Hazard values are used to estimate the incidence or potential effect as a function of human exposure to the hazardous agent


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DESCRIPTION OF THE TRADITIONAL APPROACH

In many cases, risk decisions on systemic toxicity have been made by the Agency using the concept of the "acceptable daily intake (ADI)" derived from an experimentally determined "no-observed-adverse-effect level (NOAEL)." The ADI is commonly defined as the amount of a chemical to which a person can be exposed on a daily basis over an extended period of time (usually a lifetime) without suffering a deleterious effect. The ADI concept has often been used as a tool in reaching risk management decisions (e.g., establishing allowable levels of contaminants in foodstuffs and water.) A NOAEL is an experimentally determined dose at which there was no statistically or biologically significant indication of the toxic effect of concern. In an experiment with several NOAELs, the regulatory focus is normally on the highest one, leading to the common usage of the term NOAEL as the highest experimentally determined dose without a statistically or biologically significant adverse effect. The NOAEL for the critical toxic effect is sometimes referred to simply as the NOEL. This usage, however, invites ambiguity in that there may be observable effects that are not of toxicological significance (i.e., they are not "adverse"). For the sake of precision, this document uses the term NOAEL to mean the highest NOAEL in an experiment. In cases in which a NOAEL has not been demonstrated experimentally, the term "lowest-observed-adverse-effect level (LOAEL)" is used. Once the critical study demonstrating the toxic effect of concern has been identified, the selection of the NOAEL results from an objective examination of the data available on the chemical in question. The ADI is then derived by dividing the appropriate NOAEL by a safety factor (SF), as follows:

ADI (human dose) = NOAEL (experimental dose)/SF. (Equation 1)

Generally, the SF consists of multiples of 10, each factor representing a specific area of uncertainty inherent in the available data. For example, a factor of 10 may be introduced to account for the possible differences in responsiveness between humans and animals in prolonged exposure studies. A second factor of 10 may be used to account for variation in susceptibility among individuals in the human population. The resultant SF of 100 has been judged to be appropriate for many chemicals. For other chemicals, with data bases that are less complete (for example, those for which only the results of subchronic studies are available), an additional factor of 10 (leading to a SF of 1000) might be judged to be more appropriate. For certain other chemicals, based on well-characterized responses in sensitive humans (as in the effect of fluoride on human teeth), an SF as small as 1 might be selected. While the original selection of SFs appears to have been rather arbitrary (Lehman and Fitzhugh, 1954), subsequent analysis of data (Dourson and Stara, 1983) lends theoretical (and in some instances experimental) support for their selection. Further, some scientists, but not all, within the EPA interpret the absence of widespread effects in the exposed human populations as evidence of the adequacy of the SFs traditionally employed.


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Reference Dose (RfD)

The reference dose (RfD) and uncertainty factor (UF) concepts have been developed by the RfD Work Group in response to many of the problems associated with ADIs and SFs, as previously outlined in Section 1.2. The RfD is a benchmark dose operationally derived from the NOAEL by consistent application of generally order-of-magnitude uncertainty factors (UFs) that reflect various types of data sets used to estimate RfDs. For example, a valid chronic animal NOAEL is normally divided by an UF of 100. In addition, a modifying factor (MF), is sometimes used which is based on a professional judgment of the entire data base of the chemical. These factors and their rationales are presented in Table 1.

The RfD is determined by use of the following equation: RfD = NOAEL / (UF x MF) which is the functional equivalent of Equation 1.

In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The RfD is generally expressed in units of milligrams per kilogram of bodyweight per day (mg/kg/day). The RfD is useful as a reference point from which to gauge the potential effects of the chemical at other doses. Usually, doses less than the RfD are not likely to be associated with adverse health risks, and are therefore less likely to be of regulatory concern. As the frequency and/or magnitude of the exposures exceeding the RfD increase, the probability of adverse effects in a human population increases. However, it should not be categorically concluded that all doses below the RfD are "acceptable" (or will be risk-free) and that all doses in excess of the RfD are "unacceptable" (or will result in adverse effects). The U.S. EPA is attempting to standardize its approach to determining RfDs. The RfD Work Group has developed a systematic approach to summarizing its evaluations, conclusions, and reservations regarding RfDs in a "cover sheet" of a few pages in length. The cover sheet includes a statement on the confidence (high, medium, or low) the evaluators have in the stability of the RfD. High confidence indicates the judgment that the RfD is unlikely to change in the future because there is consistency among the toxic responses observed in different sexes, species, study designs, or in dose-response relationships, or that the reasons for existing differences are well understood. High confidence is often given to RfDs that are based on human data for the exposure route of concern, since in such cases the problems of interspecies extrapolation have been avoided. Low confidence indicates the judgment that the data supporting the RfD may be of limited quality and/or quantity and that additional information could result in a change in the RfD


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Derivation of RfD

  • Adequate human data (if available): Used to establish RfD

  • Limited or no human data:

  • Animal data used

  • Involves professional judgment including relevancy of animal model used to humans, comparative metabolic data, comparative pharmacokinetic data

  • Lowest-observed-adverse-effect-level

  • No-observed-adverse-effect-level


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Calculation of RfD human dose from animal data

  • When endpoint non-carcinogenic

  • Estimate NOEAL or LOEAL

  • Then divide by “appropriately chosen” sum of uncertainty and modifying factors

  • Select highest NOEAL or lowest LOAEL for most sensitive animal species (e.g. thalidomide)

  • Recent EPA approach- NOEL= failure to achieve statistical significance


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Derivation of RfD

  • Uncertainty factors

  • RfD derived from NOAEL or LOAEL by application or uncertainty factors (UFs)

  • UF of 10 is used to account for variation in the general population and intended to protect sensitive populations

  • UF of 10 is used when extrapolating from animals to humans to account for interspecies variability

  • UF of 10 is used when a NOAEL is derived from a sub-chronic study instead of a chronic study

  • UF of 10 is used when a LOAEL is used instead of a NOAEL

  • Modifying factor (mf):

  • An MF ranging from > ) to 10 is included to reflect a qualitative professional assessment of additional uncertainties in a critical study and in the entire data base for the chemical not addressed in the above uncertainty factors

  • RfD : NOAEL or LOAEL/UFxMF mg/kg


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1.6. HYPOTHETICAL, SIMPLIFIED EXAMPLE OF DETERMINING AND USING RfD

1.6.1. EXPERIMENTAL RESULTS

Suppose the U.S. EPA had a sound 90-day subchronic gavage study in rats with the data in Table 2:

TABLE 2

Hypothetical Data to Illustrate the Reference Dose Concept

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Dose Observation Effect Level mg/kg/day

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0 Control--no adverse effects observed –

1 No statistically or biologically NOEL significant differences between treatedand control animals

5 2% decrease* in body weight gain (not NOAEL considered to be of biological significance); increased ratio of liver weight to body weight; histopathology indistinguishable from controls; elevated liver enzyme levels

25 20% decrease* in body weight gain; LOAEL increased* ratio of liver weight to bodyweight; enlarged, fatty liver with vacuoleformation; increased* liver enzyme levels------------------------------------------------------------------------------

*Statistically significant compared to controls.


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1.6.2. ANALYSIS

1.6.2.1. Determination of the Reference Dose (RfD)

1.6.2.2.1. Using the NOAEL

Because the study is on animals and of subchronic duration,

UF = 10H x 10A x 10S = 1000 (Table 1).

In addition, there is a subjective adjustment (MF) based on the high number of animals (250) per dose group: MF = 0.8.

These factors then give UF x MF = 800,

so that RfD = NOAEL/(UF x MF) = 5/800 = 0.006 (mg/kg/day).

1.6.2.1.2.

Using the LOAEL

If the NOAEL is not available, and if 25 mg/kg/day had been the lowest dose tested that showed adverse effects,

UF = 10H x 10A x 10S x 10L = 10,000 (Table 1).

Using again the subjective adjustment of MF = 0.8,

one obtains RfD = LOAEL/(UF x MF) = 25/8000 = 0.003 (mg/kg/day).


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Recent proposal to use

  • Benchmark Dose (BD), rather than NOAEL or NOEL

  • BD= statistical lower confidence limit on the dose producing some predetermined, relatively small increase in the risk


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Reference doses (RfDs) and acceptable daily intakes (ADIs) are derived by dividing NOAELs by uncertainty or modifying factors. Those factors represent a default approach to account for animal-to-human and average-to-sensitive population extrapolation or extrapolation from inadequately designed experiments. If all doses tested produce a response a lowest-observed-adverse-effect level (LOAEL) is used and a safety factor of 10 is applied. Those traditional approaches are compared with benchmark-dose methods in which a curve-fitting procedure is used to find a dose that produces a specific effect. Confidence limits are generated around that dose, which is set at the lower confidence limit to produce a specified percentage change in response. The benchmark dose (BMD) is used to calculate a reference dose.

The method is used for noncancer end points. Although the majority of applications of the BMD approach are related to developmental toxicity, it has also been applied to reproductive toxicity, neurotoxicity, and cancer. The method has been most thoroughly evaluated with reference to developmental toxicity in a series of 4 papers and technical documents by Faustman, Allen, Kavlock, and Kimmel that analyzed over 1825 experimental end points. The BMD method offers an alternative to traditional NOAEL approaches and is in general no more conservative than the use of NOAELs and includes a confidence-limit calculation. A log-logistic model for developmental toxicity has several advantages, and BMD values based on a safety factor of 5 with this model are similar to both continuous and quantal NOAEL values (without confidence limits). Traditional safety-factor approaches used for RfD calculation based on LOAEL values are over-conservative; a factor of 5 is more appropriate than a factor of 10. NOAEL values are not "riskfree" but represent effect levels ranging from below 5% up to 20% effect. That illustrates an important advantage of BMD approaches: a regulatory limit can be consistently set at a given response level rather than being dictated by study design. The BMD method rewards adequately designed experiments by setting higher BMDs, which is in direct contrast to the NOAEL approach. With curve-fitting procedures, the calculation of RfDs is no longer constrained to be one of the experimental doses tested. BMD methods will allow for easy transition to truly biologically based dose-response models when such models are developed.


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Case studies of Dioxin

  • To develop a risk assessment from the known hazard information, effects in animals or humans have to be selected that are relevant to humans at low doses.

  • Is a threshold likely?

  • With dioxins it was considered that most of the toxicity was mediated by the AHR i.e. a threshold was probably involved, and thus a NOEL + uncertainty factor approach was suitable.

  • Find the lowest dose that gives a NOEL or if not a LOEL has to be identified.

  • What is the criteria for exposure/dose level?


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What to choose for human study

to provide a NOEL/LOEL?

It was concluded that the available human data was not sufficiently rigorous for establishment of a tolerable daily intake.

  • Epidemiological did not reflect the most sensitive population seen in animal studies.

  • Too many confounding factors in exposure assessments to be sure due to dioxins.

  • Importantly, exposure of humans did not reflect UK situation where most likely from food.

http://www.foodstandards.gov.uk/committees/cot/summary.htm


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Animal studies

  • Because COC had decided that the mechanisms of cancer (whatever these may be) were threshold based, all toxicological endpoints could be examined to find the most sensitive for TCDD toxicity and this would also cover increased cancer risk.

  • In fact, very few studies could found that were in accord with modern criteria for identifying NOEL/LOEL. Of course many others were extremely good science for mechanistic and susceptibility interpretations but not suitable here.

  • The most sensitive endpoints appeared to be on the developing reproductive systems of male rat fetuses exposed in utero.

  • Despite inconsistencies between studies on some endpoints, it was considered that effects on sperm production and morphology represented the most sensitive effects that could be used for deriving a Tolerable Daily Intake.

  • Sperm reserve in men is much less than the rat and thus may be highly relevant to humans.


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What studies to use for TDI?

  • 3 studies on sperm quality were available but none perfect

  • A variety of exposure routes and endpoints and what dioxin levels present in tissues.


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Use of body burden

  • Rodents require higher doses (100-200-fold) to reach the same equivalent body burdens as in humans on exposure to food etc (differences in toxicokinetics etc).

  • A consensus view is that body burden is the more appropriate parameter for comparison between species.

  • The data of Hurst et al (2000) has given the distribution of TCDD in maternal and fetal tissue on Gestation Day 16 after single dose on D15 and chronic dosing before mating. This allows toxicodynamic and toxicokinetic estimates of maternal v fetal levels depending on dose route and timing.

  • Using the two lowest doses a ratio of 2.5 was calculated to be used in estimates of body burden from single dose and subchronic exposure in other dosing studies.


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Stolen from JC Larsen and Andy Renwick!


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Calculation of TDI

  • The study of Faqi et al (1998) was chosen as the most suitable for estimation of TDI although some problems and no NOEL but the lowest LOEL i.e. a loading dose then a maintenance dosing regime.

  • Using the previous factors the subcutaneous dosing dosage regimen of Faqi et al was converted to a steady state maternal burden on GD16 at the LOEL.

  • This was estimated as 33 ng/kg bw.


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  • With the study of Faqi et al as the most suitable available for TDI estimation. An uncertainty factor of 1 was used for interspecies differences in toxicokinetics because of using body burdens not dose.

  • An uncertainty factor of 1 was used for interspecies differences and human variability in toxicodynamics on the basis that rats may be more sensitive than humans but the most sensitive humans may be as sensitive as rats.

  • An uncertainty factor of 3.2 for human variability in toxicokinetics to allow for increased accumulation in the most susceptible individuals (for dioxins with ½ lives less than TCDD).

  • An uncertainty factor of 3 to allow foruse of LOEL rather than NOEL

  • Thus total of 9.6 (3 x 3.2 x 1 x 1) uncertainty factor


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  • Using the overall uncertainty factor of 9.6 and the calculated maternal steady-state body burden from the study of Faqi et al (LOEL = 33ng/kg/bw) gives a tolerable human equivalent maternal body burden of 3.4 ng/kg/bw.

  • Putting this into daily intake (pg/kg/day)

    = body burden(pg/kg bw) x ln2

    bioavailability x ½ life in days

    = 3400 x 0.693

    0.5 x 2740 (7.5years)

    = 1.7 pg/kg/day


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  • This TDI was rounded to 2 pg WHO TEQ/kg bw per day

    based on developing male reproductive system and maternal body burden

  • WHO (1998) 1-4 pg WHO TEQ/kg bw per day

  • SCF 14 pg WHO TEQ/kg bw per week

  • JECFA 70 pg WHO TEQ/kg bw per month

  • COT considered is adequate to protect against cancer and cardiovascular effects.

  • UK consumer levels are falling but TDI is near the the value for the average consumer and lower than 97.5 percentile


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Is this it? End of story

There actually many uncertainties

  • Dose-additivity is fundamental to the TEF idea and a reasonable idea; however we are still far from sure that this applies in the complex mixtures pertinent to human exposures. Dose reponses.

  • TEFs are mostly derived from animal data, are they appropriate for humans? e.g. carcinogenicity


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NCEH/ATSDR and risk assessment

  • Provide data on hazards, exposures, and dose-response.

  • Use standard risk assessment techniques to establish Minimal Risk Limits (MRLs) and safe exposure values for Chemical Demilitarization.

  • Establish public health guidelines and programs (i.e. Pb Poisoning, emergency response, and health assessments)


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Carcinogens

  • Different Types of Carcinogens


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Obstacles to the Identification for Human Cancer

  • The long latent period between onset of exposure to causative agents and overt appearance of the disease.

  • The multistage nature of carcinogenesis.

  • The likelihood that most human cancers result from a complex interaction between multiple environmental and endogenous (genetic, host) factors.


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Chemical Carcinogenesis

  • The term chemical carcinogenesis is generally defined to indicate the induction or enhancement of neoplasia by chemicals. Although in the strict etymologic sense this term means the induction of carcinomas, it is widely used to indicate tumorigenesis. In other words, it includes not only epithelial malignancies (carcinomas) but also mesenchymal malignant tumors (sarcomas) and benign tumors. The extension to benign tumor is justified because no carcinogen that produces only benign tumors has been discovered.


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Chemical Carcinogenesis Continued

  • It is generally agreed (e.g., WHO, 1969) that the response of an organism to a carcinogen may be in one or more of these forms:

  • 1.An increase in the frequency of one or several types of tumors that also occur in the controls

  • 2.The development of tumors not seen in the controls

  • 3. The occurrence of tumors earlier than in the controls

  • 4. An increase in the number of tumors in individual animals, compared to the controls


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Exposure to Mixtures of Chemicals

  • Independent Effects: Substances qualitatively and quantitatively exert their own toxicity independent of each other.

  • Additive Effects: Materials with similar qualitative toxicity produce a response which is quantitatively equal to the sum of the effects produced by in the individual constituents.

  • Antagonistic Effects: Materials oppose each other’s toxicity, or one interferes with the toxicity of another; a particular example is that of antidotal action.

  • Potentiating Effects: One material, usually of low toxicity, enhances the expression of toxicity by another; the result is more severe injury than that produced by the toxic species alone.

  • Synergistic Effects: Two materials, given simultaneously, produce toxicity significantly greater than anticipated form that of either material; the effect differs from potentiation in that each substance contributes to toxicity, and the net effect is always greater than additive.


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Carcinogenic Chemicals

  • An IARC Working Group (IARC, 1987) concluded that the following agents are carcinogenic to humans: (aflatoxins, aluminum production, 4-aminobiphenyl, analgesic mixtures containing phenacetin, arsenic and arsenic compounds, asbestos, auramine, azathioprine, benzene, benzidine, betel quid with tobacco, chlornaphazine, chlorormethyl methyl ether, boot and shoe making, 1,4-butanediol dimethanesulfonate, chlorrambucil, Methyl-CCNU, chromium compounds, coal gasification, coal-tar pitches, coal tars, coke production, cyclophosphamide, diethylstibestrol, erionite, estrogen replacement therapy, estrogens (nonsteroidal and steroidal), furniture and cabinet making, hemtite mining, iron, isopropyl alcohol, magenta, mustard gas, 2-naphtylamine, nickel and nickel compounds, oral contraceptives, the rubber industry, shales oils, soots, talc containing asbestiform fibers, tobacco products, tobacco smoke, treosulphan, vinyl chloride


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Common Types of Food Additives

  • Antioxidants: Prevent fats from turning rancid and fresh fruits from darkening during processing; minimize damage to some amino acids and loss of some vitamins (examples: BHA, BHT, propylgallate)

  • Bleaching Agents: whiten and age flour (examples: benzoyl peroxide, chlorine, nitrosyl chloride

  • Emulsifiers: To disperse one liquid in another; to improve quality and uniformity of texture (examples: lecithin, mono- and diglycerides, sorbitan)

  • Acidulants: Maintain acid-alkali balance in jams, soft drinks, vegetables, etc., to keep them from being too sour

  • Humectants: Maintain moisture in foods such as shredded coconut, marshmallows, and candies (sorbitol, glycerol, propylene, glycol

  • Anti-caking compounds: Keep salts and powdered foods free-flowing (calcium or magnesium silicate, magnesium carbonate

  • Preservatives: Control growth or spoilage organisms (sodium propionate, sodium benzoate, propionic acid)

  • Stabilizers: Provide proper texture and consistency to ice cream cheese spreads, salad dressings, syrups (gum arabic, guar gum, carrageenan, methyl cellulose, agar-agar


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Carcinogenic Chemicals

  • An IARC Working Group (IARC, 1987) concluded that the following agents are carcinogenic to humans: (aflatoxins, aluminum production, 4-aminobiphenyl, analgesic mixtures containing phenacetin, arsenic and arsenic compounds, asbestos, auramine, azathioprine, benzene, benzidine, betel quid with tobacco, chlornaphazine, chlorormethyl methyl ether, boot and shoe making, 1,4-butanediol dimethanesulfonate, chlorrambucil, Methyl-CCNU, chromium compounds, coal gasification, coal-tar pitches, coal tars, coke production, cyclophosphamide, diethylstibestrol, erionite, estrogen replacement therapy, estrogens (nonsteroidal and steroidal), furniture and cabinet making, hemtite mining, iron, isopropyl alcohol, magenta, mustard gas, 2-naphtylamine, nickel and nickel compounds, oral contraceptives, the rubber industry, shales oils, soots, talc containing asbestiform fibers, tobacco products, tobacco smoke, treosulphan, vinyl chloride


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Objectives of Monitoring Animal Sentinels

  • The primary goal is to identify harmful chemicals or mixtures in the environment before they might otherwise be detected through human epidemiologic studies or toxicologic studies in laboratory animals.

  • Data collection to estimate human health risks

  • Identify contamination of the food chain

  • Determine environmental contamination

  • Identify adverse effects on the animals


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Carcinogenic Effects

  • Slope factor

  • weight-of-the evidence

  • Are the data most commonly used to assess potential human carcinogenic risks

  • Non-threshold effects


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Generation of Slope Factor

  • Quantitative relationship between dose and response

  • Slope Factor is “the plausible upper-bound lifetime probability of an individual developing cancer as the result of exposure to a particular level of potential carcinogen

  • The actual risk is probably less than the estimate and could even be zero

  • Extrapolating to lower doses

  • Linearized multistage model (q1*)

  • Slope Factor = risk per unit dose, = risk per mg/kg-day


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Dose-Response Assessment

  • 1. Metabolism often different high to low dose, e.g. high dose overwhelm detoxification systems/beyond a certain dose no more effect, organ can only convert so much to active carcinogen

  • 2. Humans may metabolize differently

  • 3. Different routes of exposure

  • 4. Genetic heterogeneity (animal inbred)

  • 5. Problems in models for low dose extrapolation


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Dose-Response Relationship

  • Once a dose-response relationship is established, and often this is done in a controlled situation such as a laboratory, one can make certain statements

  • If the dose is “x”, then the response should be “y”.

  • A major problem confronting risk assessors when trying to apply the dose-response relationship to an actual “real-world” problem is the question of what dose as representative of the actual situation.

  • The process of measuring or estimating the intensity, frequency, and duration of human contact with agents currently present in the environment or the hypothetical contact that might arise from their release in the environment.


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Dose-response assessment information in the risk characterization

  • How well do the models used for dose-response represent what we know about mechanism?

  • For example, if linearity has been assumed for the “unobserved range” for PCBs, then evidence for receptor-mediated non-linearity in the dose-range of interest should be discussed.


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Dose-response assessment information in the risk characterization

  • The basis for interspecies extrapolation methods used (pharmacokinetic models or default rules)

  • Route considerations

  • Is the route of studies used for dose-response the same as that expected for humans under the scenario in question?

  • “Route” includes dosing regimen (gavage, intermittent exposures, timing of exposures).


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Dose-response assessment information in the risk characterization

  • Duration considerations (Correspondence between exposure durations expected for humans and those used in the studies used to describe dose-response)

  • Variability in dose-response

  • Variability in susceptibility (immunotoxic effects may have greater variability)

  • Interactions between toxicants.


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What have we left out by our study selection process?

  • Describe the weight of evidence that the chosen study accurately describes dose-response

  • Also describe weight of evidence for “no effect”

  • There are often studies showing both positive and negative results, but we use only the ones with positives results.

  • We bias towards choosing studies with lower LOAELs.

  • For this reason, risk characterization should point out the presence, quality, and findings of other studies in the same dose range as the one chosen to set dose response


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