Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (2001) / Chapter Skim
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2 Derivation of AEGL Values
2 Derivation of AEGL Values
Pages 34-123
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From page 34... ...
Therefore, to avoid the onset of these adverse effects, the values should not be exceeded during the specified exposure durations. Three tiers of AEGLs distinguished by varying degrees of severity of toxic effects are developed for each of the five exposure durations.
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From page 35... ...
Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. 2.2 EMPIRICAL TOXICOLOGIC ENDPOINTS AND METHODS FOR DETERMINING EXPOSURE CONCENTRATIONS USED TO DERIVE AEGLs 1, 2, AND 3 The selection of the biologic endpoints that serve as the thresholds for each ofthe AEGL severity levels are based on the definitions for the community emergency exposure levels (CEELs)
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From page 36... ...
Rather, they are considered threshold levels that represent an estimated point of transition and reflect the best efforts to establish quantitatively a demarcation between one defined set of symptoms or adverse effects and another defined set of symptoms or adverse effects. Therefore, in the development of AEGEs, the NAC/AEGL Committee selects the highest exposure level from animal or human data where the effects used to define a given AEGL tier are not observed.
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From page 37... ...
it does not consider the slope ofthe exposure-response relationship and subjects the risk assessor to using the possibly arbitrarily selected exposure levels chosen in the face of an unknown exposure-response relationship. Under some conditions, especially when only a small number of animals are exposedper exposure, the NOAELcouldbe alevel associated with significant adverse health effects (Leisenring and Ryan 1992~.
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From page 38... ...
The mean NOAEL/BMC ratios for the 1%, 5%, and 10% response were 1.60, 1.16, and 0.99, respectively, when using a probit analysis, and 3.59, 1.59, and 1.17, respectively, when using the Weibull analysis. It is interesting to note that comparable means from a Weibull analysis of developmental toxicity data were considerably greater, the developmental toxicity means of the NOAEL/BMC ratios were 29, 5.9, and 2.9 (Allen et al.
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From page 39... ...
If the data are insufficient for a meaningful statistical analysis to use that approach, then the level will be determined empirically from experimental data. 2.2.2 Selection of Health-Effect Endpoints for AEGL-l, AEGL-2, and AEGL-3 In addition to the working definitions ofthe three AEGL tiers, this section includes a summary of the specific biologic endpoints used to establish the AEGL values for individual chemicals.
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From page 40... ...
. In some people, that exposure level could result in mild lacrimation or coughing.
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From page 41... ...
. Tfan accident occurs andpeople smell or otherwise "detect" a chemical, the extent ofthe concentration range between AEGL- ~ and AEGL-2 values provides useful information and insight into the estimated margin of safety between a level of detection or mild sensory irritation (AEGL- ~ ~ and a level that may impair escape or lead to a serious long-term or irreversible health effect (AEGL-2~.
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From page 42... ...
For example, the highest experimental exposure levels that did not cause (a) sensory irritation, (b)
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From page 43... ...
The highest experimental exposure levels that did not cause decreased hematocrit, kidney pathology, behavioral changes, or lethality (effects observed at higher exposures were above the definition for AEG16-2) have been used as the basis for determining AEGL-2 values.
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From page 44... ...
value, but an LC50 value was determined and all exposure levels caused lethality, a fraction of the LCso value is used to estimate the threshold for lethality. Tn all cases, the exposure-response curve was steep, and the LCso value was divided by 3.
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From page 45... ...
When data are insufficient to estimate the highest exposure that does not cause lethality, exposure levels that cause severe toxicity in the absence of lethality are used in the selection of exposure levels to set AEGL-3 values.
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From page 46... ...
2.3 GUIDELINES AND CRITERIA FOR TlIE SEARCH STRATEGY, EVALUATION, SELECTION, AND DOCUMENTATION OF KEY DATA AND SUPPORTING DATA USED FOR THE DERIVATION OF AEGL VALUES 2.3.1 Search Strategy The literature search strategy focuses on three general sources of information: (1) electronic databases, primarily peer-reviewed journals, and government databases; (2)
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From page 47... ...
INTEGRATED RISK INFORMATION SYSTEM (IRIS) IRIS contains data from EPA in support of human hearth risk assessment, focusing on hazard identification and dose-response assessment for specific chemicals.
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From page 48... ...
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Low-Dose Extrapolation of Cancer Risks, S
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From page 49... ...
Most often, the data represent acute toxicity data from controlled inhalation exposure studies available from private industry or other organizations in the private sector of all nations that may or may not be published in a peer-reviewed journal.
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From page 50... ...
2.3.2 Evaluation, Selection, and Documentation of Key and Supporting Data As a detailed interpretation and supplementation of the NRC (1993a) guidelines, the NAC/AEGL Committee has developed guidelines for evaluating the quality of studies to be used in the calculation of proposed AEGL values.
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From page 51... ...
Additionally, all supporting data and information important to the derivation of an AEGL value are obtained solely from the primary references. These data include those used to provide a "weight-of-evidence" rationale in support of the AEGL value derived.
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From page 52... ...
In the absence of inhalation data to derive an AEGL value, the NAC/AEGL Committee may use toxicity data from other exposure routes if there are adequate data to perform scientifically credible route-to-route extrapolations. In the absence of acceptable data, the committee will refer the chemical for toxicity testing.
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From page 53... ...
Further, recent studies that followed such guidelines may not include that fact in the publication. Although human data may be important in deriving AEGL values that protect the general public, utmost care must be exercised to ensure first of all that such data have been developed in accordance with ethical standards.
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From page 54... ...
3. Only human data from studies that meet the ethical standards discussed in the "Evaluation, Selection, and Documentation of Key and Supporting Data" section ofthis SOP manual will be used in the derivation of AEGL values.
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From page 55... ...
Yes v w Selected as Key Study | Reject based on major defiaenaes in specific selection criteria No Does not represent the best key or supporting studies based on adherence to specific selection Patina No Good supporting data but does not represent the best key studies I >a Not Included in TED Background Information ># Supporting Study Derivation of one or more Acute Exposure Guideline Levels FIGURE 2-1 Decision tree for the selection of key and supporting studies.
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From page 56... ...
5. Toxicity data from routes of exposure other than inhalation generally will not be used as key or supporting data.
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From page 57... ...
The summary statements should address the adequacy of the data by AEGL tier. 2.4 DOSIMETRY CORRECTIONS FROM ANIMAL TO HUMAN EXPOSURES When extrapolating from observed responses in animals to predicted human responses, the relationship between nominal exposure concentration and delivered dose to the target tissue is of concern.
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From page 58... ...
the RfC dosimetry corrections from animal to man are based on theoretical constructs that have not been confirmed and validated with experimental data; (2) some ofthe RfC assumptions are questionable and can have a significant impact upon the calculated dosimetry correction between animals and humans.
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From page 59... ...
Of concern is the fact that when dosimetry adjustments are made between rodents and humans for toxicity to the pulmonary region, the delivered dose to the human is predicted to be about 3 times less than the mouse for an equivalent nominal exposure concentration. Using this method in the absence of supporting empirical data could seriously underestimate human sensitivity.
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From page 60... ...
If the minute-volume-tobody-weight correction for dosimetry, which assumes ~ 00°/O absorption, were used in these cases, the estimated human exposure equivalent to the rodent would be too high, leading to an underestimate of the toxicity and the derivation of AEGL values that are not protective of the human population. Another approach to dosimetry correction may be that used by EPA when extrapolating from animal cancer bioassays to theoretical excess human cancer risk levels for lifetime exposures (EPA 1992~.
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From page 61... ...
When this adjustment for breathing rate is combined with the adjustment for toxicity (EPA 1992) , the two cancel each other out and one is left with the conclusion that equivalent exposure concentrations result in equivalent outcomes in animals and humans.
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From page 62... ...
Ace. Interspecies and intraspecies UFs have been used in the development of "safe" or threshold exposure levels for chronic, noncancer toxicity by health organizations throughout the world.
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From page 63... ...
These techniques can be used to assess variability from differences in individual exposure and susceptibility for specific risk assessments to reduce the uncertainty in estimating the real variability that exists in a population (Hattie and Burmaster ~ 994; Hattis and Barlow 1996~. The use of UFs in the development of AEGL values is designed to protect the general public, including susceptible subpopulations, from short-term exposures to acutely toxic chemicals.
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From page 65... ...
EPA considers the RfD to be an estimate (with uncertainty spanning perhaps an order of magnitude of a daily exposure to a human population, including susceptible subpopulations) that is likely to be without an appreciable risk of deleterious effects during a lifetime.
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From page 67... ...
summarized the status of UFs in noncancer risk assessments and discussed the use of"data-derived" UFs by various health organizations, EPA, and Health Canada. These authors presented data on interspecies and inkaspecies variability of response that supported the use of Tower UFs that are protective of human health.
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From page 68... ...
Based on the considerations presented above, the acceptance and use of default UFs based on chronic exposure data are carried out only after careful evaluation of chemical specific data for single exposures. However, the concepts, ideas, and approaches to developing UFs that have emanated from the chronic exposure studies ofthe past ~ 0 years are valuable in the development
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From page 69... ...
subdivided the interspecies and intraspecies UFs into two components to address toxicokinetics and toxicodynamics separately. Although supporting data for this concept stem from chronic animal feeding studies and in vitro cell cultures, the concept of considering the kinetics and
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From page 70... ...
UF of lO-fold when only animal data were available or when the route of human exposure differed from the study. However, the population for which SMACs is intended (astronauts)
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From page 71... ...
2.5.3.2 Interspecies UFs NAC/AEGL Committee Guidelines The NBC (1993a) provides guidance on approaches to selecting the most appropriate species for deriving AEGL values.
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From page 72... ...
3. The qualitative and quantitative range of responses of the species tested.
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From page 73... ...
2.5.3.2.7 Inadequate Data The UF for interspecies response adjustment is 10 when there are inadequate data or insufficient information about the chemical or its mechanism of action to justify an alternative UF. The rationale for the selection of a UFshould include the following: Discussion ofthe inadequacy ofthe data that are the basis for aUF of 10.
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From page 74... ...
Citations and explanations of the human data and how it relates to the AEGL value derived with a UF selected on the basis of the existing guidelines. 2.5.3.2.9 A Multiple Exposure Study Used to Set the Level in cases in which an AEGL value is derived from a multiple exposure study, because the data set for a single exposure is lacking, the multiple exposure data are considered an inherently conservative estimate.
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From page 75... ...
In all cases, the NOAEL represents the highest exposure level from animal data in which the effects used to define a given AEGL tier are not observed. 2.5.3.3 Intraspecies UFs Used in the Development of AEGL Values— Discussion Tntraspecies UFs are used to address the variability in biologic response that exists within a human population exposed to a toxic agent.
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From page 76... ...
An adjustment factor of 10 was adequate to reduce the response from a dose killing 50% of the animal population to a level that would kill only the most susceptible members of the inbred rat population in 92% of the chemicals studied. These data support the contention that a 10-fold UF is adequate in many instances to account for intraspecies differences in response to acute exposures.
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From page 77... ...
Approximately 86% of the ratios were less than 10, indicating that this factor is adequate to account for differences in response to chemical exposure between adult and young in most cases but may be insufficient for ~ 4°/O ofthe cases. In these studies, the comparison was made from the median response.
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From page 78... ...
They do not measure how far the tail for response goes beyond the lowest dose in the population measured, nor the response of different populations. Another consideration is the fact that these data represent measures of toxicokinetic variables that may not directly reflect the threshold of toxicologic response to chemical exposure.
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From page 79... ...
(l 999) indicates that a human intraspecies UP of 10 would be protective of susceptible subpopulations and may be overly conservative in many instances.
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From page 80... ...
As previously stated, this type of study gives a measure of response between groups within a population but not the variability within each group. Intraspecies UFs are used to address the variability in biologic response that exists within a human population exposed to a toxic agent.
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From page 81... ...
All information on the chemical, its mechanism of action, structurally related chemical analogues, a discussion of the weight of evidence, and informed professional judgment are used when determining UFs. 2.5.3.3.l Range of Susceptibility The definition and intended application of AEGL values make distinctions between susceptible and "hypersusceptible" individuals.
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From page 82... ...
In general, since there is little or no information regarding the responses of transiently hypersusceptible individuals to chemical exposures, the corresponding AEGL values might not be protective for this group. During the past 15 years, a wide range of symptoms and complaints in patients thought to be related to extreme sensitivity to Tow levels of diverse and often nonquantifiable chemical exposures have been reported.
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From page 83... ...
1999~. Although most researchers contend that symptoms characteristic of chemical sensitivities exist, they agree that symptoms may be exaggerated and may be "differentially precipitated by psychosocial events or stress, or by different physical or chemical exposures" (Ashford 1999~.
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From page 84... ...
~ 999; Brown-DeGagne and McGlone 1999~. As a result of the considerations presented here, it is not believed that MCS represents a viable scientific basis for developing AEGL values, including further adjustments for susceptible subpopulations, at the present time.
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From page 85... ...
, and impaired renal or immunologic function (e.g., AIDS and systemic lupus erythematosus) Hypersusceptible subpopulations are considered to comprise those individuals whose reactions to chemical exposure are unique and idiosyncratic; lie outside the range of distributions expected for the general population, including susceptible subpopulations; and constitute a relatively small component of the general population.
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From page 86... ...
In the absence of data on the chemical in question, the use of structurally related chemicals and scientific judgment may be used to select UFs that provide protection for the public health. 2.5.3.3.4 Estimating the Range of Variability in a Human Population The NAC/AEGL Committee estimates the range in variability of response to specific chemical exposures primarily on the basis of quantitative human data.
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From page 88... ...
All information on the chemical, including its mechanism of action, the biologic responses, physical and chemical properties, data on structurally related chemical analogues, and toxic endpoints in question, is considered and informed professional judgment is used when determining appropriate UFs. Information about similarities and differences in toxicokinetics and toxicodynamics is used when available to modify the UF used.
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From page 89... ...
2.5.3.4.2 Susceptible Individuals Used If individuals representative of a susceptible subpopulation are used as subjects in controlled humans studies, and the AEGL is to be calculated based on effects observed in those individuals, an intraspecies UF of less than 10fold may be used. The rationale for the selection of this UF should include the following: 1.
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From page 90... ...
2. Discussion of why the response to chemical exposure is unlikely to differ between healthy and susceptible individuals and whether metabolic or physiologic differences are likely to be an issue.
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From page 91... ...
2.5.3.4.6 UFs That Result in AEGL Values That Conflict with Actual Human Exposure Data When AEGL values are initially derived, the candidate range of values is compared with the known spectrum of supporting data on the chemical. In a weight-of-the-evidence approach, conflicts between the candidate AEGLs (generally derived from animal data)
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From page 92... ...
Therefore, AEGL development usually requires extrapolation from the reported exposure duration and chemical concentration of a toxic endpoint to an equivalent concentration for an AEGL-specified exposure period. This section discusses that concept, the published scientific literature, the methodologies used for extrapolation, and examples of the application of these methodogies to specific chemicals for the development of AEGL values.
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From page 93... ...
if data are not available for empirically deriving the exponent n, the NAC/AEGL Committee identifies the most appropriate value for n by comparing the resultant AEGL values derived using n = 1 and n = 3. The value of n = ~ has been used historically by others and results in rapid reductions in concentrations when extrapolated to longer exposure periods and rapid increases in concentrations when extrapolated to shorter exposure periods.
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From page 94... ...
(1986~. In selecting a value for n when the derivation of n is not possible, the NAC/AEGL Committee evaluates the resultant AEGL values determined with either the upper or the lower boundary value of n (l
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From page 95... ...
As a result ofthe potential uncertainties in dose-response relationships associated with exposure durations of less than TO-min (a transition period in breathing rate, physiologic responses, scrubbing efficiency/saturation, chemicar-specific issues, and other factors) and in the absence of definitive supporting data, extrapolations using 4-h and 8-h empirical data generally are not extended to 10-min AEGL values but are assigned the same value as the 30min AEGL.
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From page 96... ...
should be determined empirically from acute inhalation exposure toxicity data on a chemical-specific basis. 2.7.3 Summary of the Approaches That May Be Taken for Time Scaling A tiered approach to generating toxicity values for time scaling is taken by the NAC/AEGL Committee to derive AEGE values from empirical data.
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From page 97... ...
TfJefinitive supporting data for ~ O-min exposures are not available when extrapolating from Ah empirical data, the 10-min AEGL generally is assigned the same value as that extrapolated for the 30-min AEGL. If no empirical exposure concentration-exposure duration relationship data are available to derive a value of n, a value of n = ~ for extrapolating from shorter to longer exposure durations and a value of n = 3 for extrapolating from longer to shorter exposure durations should be tested initially.
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From page 98... ...
2.7.5 Derivation of Values of n When Adequate Empirical Data Are Available for Durations Other Than the AEGL-Specified Exposure Durations A key element in the procedure of time scaling is the use of a value or values for n in the equation Cn x t = k. If empirical data for exposure durations other than the AEGL-specified exposure periods are available to quantify the exposure concentration-exposure duration relationships for a health-effect endpoint, including lethality, the value of n should be derived using the method of calculation described in this section.
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From page 99... ...
However, the validity and, hence, the values of n will depend on many factors, including the scientific soundness ofthe exposure concentration-duration data, the length ofthe empirical exposure durationts) relative to the AEGL-specified exposure periods, and the known or perceived similarities in effects and mechanism of action of the chemical at the reported exposure concentrations and durations.
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From page 100... ...
In the assessment of empirical data reported by ten Berge et al.
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From page 101... ...
/n + (-fin) x log t, where C is the predicted value of the concentration to cause an effect at exposure duration t.
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From page 102... ...
As stated earlier, it must be emphasized that when deriving or selecting a value for n, the NAC/AEGL Committee evaluates the resultant AEGL values within the context of other supporting data to determine the reasonableness of the extrapolated values. This is done even when the value of n is derived from empirical data that describe the exposure concentration-duration relationship.
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From page 103... ...
The value of n is then used in the equation Cn x t = k to extrapolate from empirically reported exposure concentrations and exposure durations to the AEGL-specified exposure durations. The committee then selects the derived AEGL values in accordance with the supporting data.
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From page 104... ...
Therefore, when extrapolating from long to short exposure durations, a value of n = 3 yields a more conservative value than any value of n that is <3. NAC/AEGL Committee develops tentative AEGL values from shorter to longer exposure durations using n = ~ in the equation On x t = k and evaluates these values with all other supporting data to `determine their scientific reasonableness.
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From page 105... ...
In instances in which the supporting data indicate that the tentative AEGL developed using a value of n = 3 is too high or too Tow, the AEGL may be adjusted to scientifically account for the supporting data. If no supporting data indicate that the derived AEGL should be adjusted, a value of n = 3 should be used to accommodate for the uncertainty of the exposure concentration-duration relationship for the shorter exposure durations.
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From page 107... ...
As stated earlier, it must be emphasized that when deriving or selecting a value for n, the NAC/AEGL Committee evaluates the resultant AEGL values within the context of other supporting data to determine the reasonableness ofthe extrapolated values. This evaluation is done even when the value of n is derived from empirical data that describe the exposure concentration-duration relationship.
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From page 108... ...
The values of n are used with the equation Cn x t = k to extrapolate from the empirically reported exposure concentrations and exposure durations to the AEGL-specif~ed exposure durations. AEGL values in accord with the supporting data are then selected.
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From page 109... ...
2. Presentation ofthe AEGL values or exposure concentrations extrapolated from data using a value of n = 1 or n = 3 and the adjustments made as a result of supporting data..
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From page 110... ...
Conversely, a value of n = 3 is used when extrapolating from longer to shorter periods, because the extrapolated values are conservative and therefore reasonable in the absence of any data to the contrary. Because of the uncertainty in ~ O-min exposure data and the absence of definitive supporting data, the lO-min AEGL is assigned the same value as the 30-min AEGL when extrapolating from 4-h or 8-h empirical data.
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From page 111... ...
The evolution and usefulness of mathematical models to accommodate new understanding or new concepts regarding the mechanisms of carcinogenesis have been summarized in two publications by the NRC: Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants MARC 1992a) , and Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances MARC 1 993a)
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From page 112... ...
As a first approximation, the default approach involves linear low-dose extrapolation from an upper confidence limit on theoretical excess risk. Further, the NRC guidance states that the determination of short-term exposure levels will require the translation of risks estimated from continuous long-term exposures to risks associated with short-term exposures.
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From page 113... ...
In each case, the theoretical excess cancer risk level used was ~ 0-4, and the derived values were determined to be lower than corresponding airborne concentrations that were estimated to cause acute toxicity. SPEGL values for exposure periods of less than 24 h of other known or suspect human carcinogens were not based on carcinogenicity.
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From page 114... ...
2.~.3 Scientific Basis for Credible Theoretical Excess Carcinogenic Risk Assessments for Single Exposures of ~ Hours or Less The NRC guidance (NRC ~ 993a) explains that AEGEs can be developed using carcinogenic risk-assessment methods for exposure durations of ~ to ~ h provided adequate data are available.
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From page 115... ...
2.~.4 Practical Issues of Using Quantitative, Carcinogenic Risk Assessments for Developing AEGLs In addition to fundamental scientific issues regarding carcinogenic risk assessments in the development of AEGL values, there are important practical
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From page 116... ...
Thus, setting AEGL values based on uncertain theoretical cancer risk estimates might lead to response measures that increase actual or total risk for the exposed population. 2.~.5 Current Approach of the NAC/AEGL Committee to Assessing Potential Single Exposure Carcinogenic Risks On the basis of the discussions and considerations presented in the earlier sections ofthis chapter on cancer risk assessment, the NAC/AEGL Committee has developed no AEGL values based on carcinogenicity.
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From page 117... ...
it is believed that information on known or suspect human carcinogens should be provided to emergency planners and responders and made available to the public even when such information is not used to set AEGL values. Therefore, the NAC/AEGL Committee will continue to provide data and information on the carcinogenic properties of chemicals in the TSDs and, in instances in which the appropriate data are available, develop quantitative cancer risk assessments at risk levels of ~ 0-4, ~ 0-5, and ~ o-6 in accordance with the NRC guidance (NRC 1993a)
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From page 118... ...
Although the NRC guidance states that multistage models could be useful for setting AEGL values, the guidance acknowledges that sufficient information may not be available to postulate the total number of stages in the cancer process and the stages that are dose-related. in these instances, the NRC guidance recommends the use of the time-weighted-average dose where the instantaneous dose D at time to is assumed to be the equivalent of the lifetime excess carcinogenic risk as daily dose D up to time t.
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From page 119... ...
However, the impact ofthe number of stem cells at the time of chemical exposure is considered as well as the net growth rate of cells that have undergone the first stage of initiation. If the first-stage initiating event creates a cell that has a net growth rate greater than that of the stem cell, then the risk of that initiating event will be greater than it would be if the initiated cell grew at the same relative rate as the stem cell.
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From page 120... ...
Thus, the cancer risk associated with a single exposure to a promoter should not be greater than that predicted for multiple exposures, and no correction to the estimated risk has to be made in this case. A major impact upon the risk assessment of the two-stage model comes from carcinogen exposure during the first stage in which the initiation event creates a cell with a greater net growth rate than the stem-cell rate.
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From page 121... ...
1986) are used to compute lifetime theoretical excess carcinogenic risk levels.
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From page 122... ...
For example, values of 14.9 and 15.1 would yield AEGL values of 10 and 20, respectively. This is a 2-fold difference for a very small difference in computed AEGL values.
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From page 123... ...
However, many inhalation studies on toxicity report the chemical concentrations in milligrams per cubic meter. In deriving AEGL values, it is assumed that the concentrations reported were measured at normal temperature and pressure (i.e., 25° C or 298° K and 760 mm Hg)
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