Dose Response and Descriptors

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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-response curves 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-eff
ect 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 gt ) 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 --------------------------
--------------------------------------------------
-- Dose Observation Effect Level mg/kg/day
-------------------------------------------------
----------------------------- 0 Control --no
adverse effects observed 1 No statistically
or biologically NOEL significant differences
between treated and 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 body weight enlarged, fatty
liver with vacuole formation 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-advers
e-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/sum
mary.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 for use 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 33 ng/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
  others 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.

41
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).

42
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