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Air Toxicology and Epidemiology
Comment: For some of the Level II concentrations, OEHHA has relied on the results of reproductive/developmental studies, in which the animals were exposed repeatedly, in some instances for the duration of gestation. OEHHA has characterized Level II as protective against "disability" due to immediate effects, such as loss of consciousness or cardiac or respiratory effects, and to other, potentially delayed health effects, such as hepatitis or reproductive and developmental effects. Development of a one-hour limit intended to be protective against potential delayed effects without consideration of the mechanism of that effect is highly questionable. The potential for these delayed effects to develop following a one-hour exposure should be evaluated only in studies with a single exposure of a similar duration. Once the duration of exposure has exceeded 24 hours or exposure is repeated for several days, mechanisms of toxicity may come into play, such that Habers Law no longer applies making the incidence of certain endpoints, such as reproductive /developmental effects, highly unlikely to occur as a result of a one-hour exposure, even at high exposure levels.
Response: While it is true that 1-hour exposure data might be useful for developing RELs based on reproductive and developmental (R/D) toxicity, such data do not exist. One would have to conduct studies in which each hour of gestation were studied separately, which is logistically impractical. Therefore, since it is reasonable to assume that R/D toxicity can occur in humans following a single exposure to a chemical with demonstrated R/D toxicity in animals, we are constrained to use the animal data available. This is what we have done in the Technical Support Document. Since there is no assumption-free mechanism to incorporate such data into human health risk assessment for acute exposures, OEHHA has adopted a scientifically-defensible and not an extreme set of assumptions.
First, we have proposed consideration of the day of exposure as the base unit for onset of R/D effects. Within the unit exposure day, OEHHA has proposed time-extrapolation to approximate an equivalent daily 1-hour exposure. It is commonly accepted that exposures to chemicals during brief, critical periods of gestation may result in R/D effects. For this reason, OEHHA considers each daily exposure to be an independent event. This assumption is obviously more valid for chemicals that do not bioaccumulate or do not have cumulative toxicity. A more sophisticated treatment of chemicals that accumulate and have some degree of cumulative toxicity is warranted but is not feasible at this time. Therefore, OEHHA has assumed that recovery between successive exposures has been achieved by the experimental animals. To assume otherwise in absence of specific data would not be health protective and would be unjustifiable both scientifically and from a public health standpoint.
For these reasons, OEHHA can not accept the suggestion in the comment that the least health-protective assumption should be used, namely assuming complete additivity of all doses received by experimental animals in order to achieve a R/D effect.
Comment: In general, when the NOAEL approach is used, if multiple NOAELs are available in one animal species, then the highest NOAEL for that animal species is used in comparison to other species NOAELs. The highest NOAEL that is lower than the lowest LOAEL is generally selected based on a comparison of the best quality studies as the NOAEL upon which to base an exposure level, because this ensures that the exposure level is based on the most sensitive endpoint. Selecting the highest NOAEL, as indicated by OEHHA, may not be protective for the most sensitive endpoint.
If the NOAEL approach is used, which is not the most appropriate methodology for deriving a one-hour exposure level, the NOAEL approach recommended by OEHHA may be less conservative than that currently recommended by the USEPA. By selecting the highest NOAEL without considering the lowest LOAEL, OEHHA approach is less conservative, which may result in a level that is not protective of the most sensitive endpoint. The types of problems encountered in defining a NOAEL can be eliminated by using the BMD approach.
Response: No specific examples are given in the comment to support these concerns. We believe that the NOAEL approach used in the Technical Support Document is fully consistent with the intent of the uncertainty factor methodology used by USEPA. It should be recognized that USEPA does not presently have any acute non-cancer reference values for routine release scenarios or corresponding methods to use for comparison.
The comment recommends using benchmark methodology in place of the NOAEL approach. Where possible, OEHHA has proposed benchmark concentration methodology for determining 1-hour exposure levels. However, most data sets do not allow for quantal dose-response benchmarks to be determined. Benchmark methodology for continuous data is being examined, but is not currently available.
Comment: An attempt should be made to develop an exponent based on the empirical data available from acute inhalation toxicity experiments, rather than attempting to use a default value for n. . . .
The analyses conducted by Ten Berge et al. (1986) examined the relationship between concentration and exposure time for predicting mortality response. OEHHA used the chemical-specific regression coefficients (n) reported by Ten Berge et al. (1986), when available, to adjust concentrations administered to humans or animals in the study selected for a duration different than one-hour. However, because these regression coefficients were derived based on mortality data, they are not applicable to other endpoints. . . .
OEHHA has apparently chosen to use a default approach, rather than consider mechanistic data or in the absence of such data, a conservative approach designed to mitigate potential overestimation of exposure concentrations. If so, that should be stated openly rather than attempting an ad hoc scientific justification based on Ten Berge et al. (1986).
Response: The comment expresses disagreement with the use of a default procedure for estimating 1-hour concentrations that cause adverse effects. It is correct that the Ten Berge et al. (1986) paper used mortality data to derive exponents of "n" for the equation Cn x T = constant. OEHHA uses the principle of the Ten Berge et al. paper without necessarily using specific values contained in the paper. OEHHA agrees with the comment that mortality data do not necessarily reflect the dose-duration response relationships for other endpoints. When specific data on the endpoints of concern existed to derive the exponential term for this relationship, we have used the data and derived "n" (see chlorine, ammonia, and phosgene as examples). The generic example given in the comment for using "mechanistic data" to derive the exponential term when response data do not exist describes differences between systemically and locally acting irritants and the usefulness of considering different mechanisms when deriving "n". While the example given contains no specific data or citations, it does point out the importance of considering biological mechanisms. The comment advocates the exchange of default values for the assumption that mechanistic information is an adequate substitute for actual exposure data. This comment overestimates the quantity and utility of "mechanistic" data for such acute exposures. Furthermore, no specific recommendations are made in the comment on how such information can be used consistently and quantitatively in estimating the exponential term.
OEHHA has derived acute exposure levels by methods that we believe are scientifically sound and based on existing data. Because data gaps exist, health-protective parameters are used. If data should become available that suggest changes to this methodology or to specific values, we will consider such data. Mechanistic data may be of use in estimating exponential terms for the modified Habers Law. However, use of such data can only produce estimates, which should be validated by actual exposure data. Until methodology exists for the incorporation of such data, we believe that the use of the health-protective values are justified.
Comment: There is no factual basis for the statement that, For acute toxicity data, the log-probit model usually provides a good fit and is generally used.
Response: The log-normal model is among the most widespread models used for toxicity testing and has traditionally been used extensively for determination of acute lethality and other dichotomous responses (Finney et al., 1971; Rees and Hattis, 1994). Furthermore, the log-normal distribution aspect of the model is biologically plausible and accounts for some degree of inter-individual variability (Rees and Hattis, 1994).
Comment: OEHHAs decision to define the BMD as a probability of a 1% response will always result in more stringent standards than the use of the NOAEL approach, resulting in an overly conservative approach. In a study by Allen et al. (1994) the experimentally derived NOAEL was compared to the BMD. Based on the work of Allen et al. (1994), of BMDs defined as a 10%, 5%, or 1% probability of a response based on quantal data, the 10% BMD level on average was closest to the NOAEL derived from the experimental data. A BMD level for quantal data based on a 1% probability of a response was on an average of 29 times lower than the NOAEL, while at the 10% probability level, the average BMD level was 3 times lower than the NOAEL. Therefore, it appears that the proposed guidance using the BMD approach will in general result in lower levels than the NOAEL approach and will be highly conservative. An estimate of exposure producing a 1% probability of response may be model dependent; however if a higher response level, such as 10%, was used, the BMD would be less model dependent. Therefore, if the BMD approach is to be used for the development of acute exposure levels, OEHHAs BMD should be defined as a probability of a 10% response, rather than a 1% response.
Response: Although our analysis shows that there is not much difference between the BC01 and the BC05, in order to be consistent with USEPA, OEHHA has changed the proposed benchmark from 1% to 5%.
It is not the goal of the benchmark dose approach to emulate results from the NOAEL approach, and the continued reliance on such comparisons is inherently flawed. Furthermore, the data upon which the comment relies is an analysis of developmental data sets by Allen et al. (1994). In their analysis, Allen et al. show that BC01 is 29-fold below the level of the NOAEL, on average. The BC05 values were also below the NOAEL, on average, by about 6-fold. However, the analysis is extremely limited due to the examination of only developmental toxicity studies. In our analyses, the BC01 is less than 2-fold below NOAELs taken from acute studies, and only about 1.3-fold below the BC05, on average, for acute responses other than developmental defects. The dose-response slope for developmental toxicity studies may not be representative for all other endpoints. It is therefore premature to conclude that the BC01 values are overly conservative based on the analysis by Allen et al. (1994).
Comment: OEHHA recommends that when using the BMD approach uncertainty factors of 10 be applied to the BMD for uncertainty involved in animal to human extrapolation and human intraspecies variability. However, because the BMD approach takes into account intraindividual variability, which is what determines the shape of the dose response, OEHHA recommends adjustments resulting in factors of less than 10. This recommendation has merit, but it should not be a rigid default recommendation, like the modifying factor of 0.3 recommended by OEHHA. The biological aspects of the response should regulate the magnitude of the uncertainty factors and/or modifying factors used, rather than setting a default value.
Response: OEHHA agrees that if "biological aspects of the response" can be specifically quantified, they should be incorporated into uncertainty factors and the existing value should be replaced. However, this needs to be determined according to the individual chemical. The comment presents no data or examples that pertain to this process.
Instead of a modifying factor of 0.3, the REL development methodology now specifies an uncertainty factor of 3 to extrapolate from a LOAEL to a NOAEL for mild sensory irritation.
Comment: The preferred approach for the derivation of acute toxicity levels based on studies of longer duration is a method similar to the method reported by Guth and associates (1991) in Appendix D of OEHHAs Technical Document.
Response: The methodology proposed by Guth and associates in 1991 and suggested in the comment has potential applications that may make it the preferred one under some circumstances. It allows the information from a large number of smaller studies reporting NOAEL or LOAEL data to be combined, therefore strengthening the conclusions reached. However, because it has not yet been approved for use by USEPA and because it is useful only for chemicals on which there are a large number of studies, it is not a recommended approach for the development of reference exposure levels.
Finney DJ. Probit analysis. Cambridge, England: Cambridge University Press; 1971.
Rees DC, Hattis D. Developing quantitative strategies for animal to human extrapolation. In: Hayes AW, editor. Principles and methods of toxicology. 3rd ed. New York: Raven Press; 1994.
Comment: For the Level I concentration, OEHHA used a regression coefficient, n, of 4.6 reported in Ten Berge et al. (1986). However, this regression coefficient (n) is based on a dose-response relationship for mortality. The use of any value based on mortality data is not usable for extrapolation to other endpoints, especially for nonsystemic endpoints, such as irritation.
Response: The comment incorrectly concludes that OEHHA used Ten Berge et al. (1986) mortality data to arrive at the exponential term of 4.6 for the time-extrapolation used in the benchmark calculation. In fact, as stated in the ammonia summary,
The value for the exponent n was empirically derived from the preceding data sets [Industrial Biotest Laboratories, 1973; MacEwen et al., 1970; Silverman et al., 1949; Verberk, 1977]. The value of n (in the formula Cn * T = K) was sequentially varied for the log-normal probit relationship analysis. Using a chi-square analysis, a value of n = 4.6 was found to be the best fit.
OEHHA therefore derived the exponential term of 4.6 using human irritation data and maximizing the goodness of fit in a series of log-normal regressions. The value reported by Ten Berge et al. (1986) for ammonia is 2, not 4.6, and is unrelated to the OEHHA value.
Comment: OEHHA used the Habers Law modification to extrapolate a one-hour concentration for the data from four studies with human irritation or "nuisance" as the endpoint and then incorporated all incidence data from the four studies into the BMD model. Normally, when the BMD approach is used, studies are evaluated to select data sets for the BMD model. All applicable data sets are then modeled individually and the data set with the best fit is generally selected for the final decision of the BMD. Other factors play a role in the selection of the BMD, such as endpoints that are most relevant to human health. In general, individual data sets from individual studies are not combined and modeled simultaneously. If the protocols of the individual studies are identical, the incidence data may be grouped and modeled together as one data set. However, the protocols from the four studies used by OEHHA for the development of the Level I REL were different. In addition, there were no control groups in any of the studies evaluated; therefore, the background in the BMD approach was assumed to be zero. Based on these considerations, the relevance of the Level I REL based on the BMD approach may be questionable. The incidence data from each of the studies considered should be modeled individually for the selection of the BMD.
Response: OEHHA derived an REL for ammonia using combined data from the 4 studies mentioned above. We believe, in this case, incorporation of several sets of human data into a single analysis better represents the human response to ammonia exposure. The 4 studies selected by OEHHA were of similar quality and experimental design. However, each was somewhat limited due to small sample sizes and number of exposure groups tested. The OEHHA analysis integrates 4 data sets in order to utilize the available data to the greatest extent, thereby decreasing uncertainty in developing an REL. The comment previously recommended a form of BC analysis by Guth et al. (1991) that combines not only studies with different protocols, but with vastly different durations, subject groups, species and severity.
Comment: OEHHA calculated the 1-hour Level I REL assuming that the LOAEL for decreases in lymphocytes and the host resistance resulted from 6 hours of exposure to 30 ppm benzene. However, based on the information reported the decrease in T-cells and B-cells was associated with 30 hours of exposure (6 hours/day for 5 days), while the decrease in host resistance was associated with 54 hours of exposure (6 hours/day for 9 days). Therefore, the derivation of an exposure level based on 6 hours of exposure in inappropriate, as well as the assumption that the effects were observed following the same duration of exposure.
Response: The comment raises the criticism that OEHHA should not use repeated dose studies of greater than 1-day for use in estimating 1-hour exposure levels. The comment is correct that the Rosenthal and Snyder study involved 6-hour, daily exposures for several days, after which the animals were killed and immunological parameters were measured. The comment recommends that full additivity of the intermittent daily doses be assumed by OEHHA for the exposure of the mice in this study. However, such an assumption is not necessarily valid scientifically, since some degree of recovery likely occurs during the 18-hour periods of benzene-free air the animals experienced between the 6-hour benzene exposures. Similarly, such an assumption is not public health protective when considering the uncertainties involved. Since measurements were not performed by the authors after single 6-hour exposures, the point cannot be proven either way, and OEHHA has chosen the more health-protective assumption in this case.
Comment: The relevance of an exposure concentration based on an immunological endpoint from a single study for use in drawing conclusions with regard to human immunotoxicity may be questionable.
Response: Animal immunotoxicity data are applicable to humans. Due to the highly conserved nature of the immune system across many species, animals are very likely appropriate surrogates for humans. In addition, immunotoxicity has been repeatedly linked with disease-resistance deficits in many animal studies, and is used by the National Toxicology Program and several pharmaceutical companies as part of routine toxicity testing. The argument that immunotoxic effects in animals do not apply to humans is no longer valid. Finally, a compound with such well-documented hematopoietic toxicity in animals and humans as benzene has more than sufficient mechanistic evidence to support concern for immunotoxicity.
Comment: OEHHA reported that the Level II concentration for benzene was based on three studies, Coate et al. (1984), Kuna and Kapp (1981), and Keller and Snyder (1988).
. . . OEHHA calculated the 1-hour Level II concentration based on the development of effects following the 4 hours of exposure; however, the animals were exposed for 60 hours (6 hours/day on days 6-15 of gestation).
Response: The severe adverse effect level value for benzene is based on the developmental toxicity study in rats by Coate et al. (1984). The comment incorrectly states that OEHHA based the severe adverse effect level on effects following a 4-hour exposure. OEHHA based the calculation of the severe adverse effect level on the 6-hour per day exposure duration in the Coate et al. (1984) study. For the same reasons as discussed above, the assumption of complete additivity for all exposures, as suggested in the comment, was not made by OEHHA.
Comment: Clear justification for the selection of 40 ppm as the NOAEL is not provided. Of the three studies evaluated by OEHHA for the development of the Level II criteria, the lowest NOAELs were reported by Keller and Snyder (1988) and Kuna and Kapp (1981). In this study, OEHHA reported that Keller and Snyder (1988) found suppression of erythropoietic precursor cells and persistent, enhanced granulopoiesis in the offspring of mice exposed to 20 ppm benzene on days 6-15 of gestation, with no hematotoxicity observed following exposure to 10 ppm benzene. In the Kuna and Kapp (1981) study, exposure to 50 ppm benzene resulted in reduced fetal weights, while no fetal effects were reported following exposure to 10 ppm benzene. These NOAELs are lower than the NOAEL of 40 ppm benzene for decreased fetal weights reported in rats following exposure for 6 hours/days on days 6-15 of gestation. The endpoints of hematotoxicity in the offspring of mice reported by Keller and Snyder (1988) would represent the most sensitive endpoint in the most sensitive species. However, the results of this study are not regarded as definitive due to limitations including small group size, lack of a dose-response relationship, and a lack of control results. OEHHAs reason for using the NOAEL from Coate et al. (1984) rather than the NOAELs of 10 ppm reported by Kuna and Kapp (1981) and Keller and Snyder (1988) is unclear. If the basis of OEHHA Level II concentration is just the Coate et al. (1984) study, OEHHA should not have included Keller and Snyder (1988) and Kuna and Kapp (1981) as part of the basis of their Level II concentration.
Response: The effects reported in the Keller and Snyder (1988) paper were, as stated by the commentator, "not definitive due to small sample size, lack of a dose-response, and a lack of control results." It is therefore unclear why the commentator proceeds to suggest the use of the Keller and Snyder (1988) study as the basis for the severe adverse effect level. OEHHA included discussion of these studies to illustrate the presence of other developmental toxicity results at concentrations near to that reported in the Coate et al. (1984) study. Consistent with the methods proposed by OEHHA, the selection of the highest reported NOAEL below a LOAEL was used as the basis for the Level II for benzene. The studies by Kuna and Kapp (1981) and Keller and Snyder (1988) were examined by OEHHA and were found to contain either higher LOAELs or lower NOAELs than that seen in the Coate et al. (1984) study. The commentator is therefore correct (page 15 of attachment) that these studies contain lower NOAELs for developmental effects. However, according to the proposed methodology, it is the highest NOAEL below a LOAEL that should be selected to avoid being overly conservative.
Comment: Selection of the Level I REL for hydrogen sulfide illustrates a limitation in the OEHHA methodology-- a lack of clear guidelines for the selection of the study or endpoint upon which to base the one-hour level. The proposed LEVEL I REL for hydrogen sulfide is 0.03 ppm based on the perceived odor threshold in 16 individuals exposed to increasing concentrations of hydrogen sulfide for an unspecified duration.
Response: The REL for hydrogen sulfide has been recalculated based on the respiratory effects observed in the study by Jappinen et al. (1990). The REL has thus been changed from 42 to 140 µg/m³.
Comment: The commentator provides several criticisms of OEHHAs REL for nickel based on immunotoxicity in mice exposed to soluble nickel chloride.
Response: The new REL for nickel is no longer based on immunotoxicity in mice, but on small decrements in airway function tests in a study of human asthmatics.
Comment: OEHHA calculated their one-hour concentration [for toluene] assuming only 6 hours of exposure to the animals during gestation. However, the results indicate that the animals could be exposed for approximately the entire gestation period, with no fetotoxic effects on the offspring. If a one-hour concentration were calculated using this study, exposure would be for at least 120 hours, assuming that the exposure during gestation was the only contributing exposure period to the fetotoxic effects observed following exposure to 2000 ppm (the higher concentration). If 120 hours of exposure were considered, using the modification of Habers Law would result in a one-hour concentration of 5477 ppm toluene. However, . . . the use of a study of this duration to determine a one-hour exposure is questionable.
Response: OEHHA acknowledges that the time-extrapolation from multiple exposures to a 1-hour exposure is not ideal. However, for a number of substances tested in developmental toxicity research, it has been shown that exposure to a dose of chemical during a critical period of development can result in adverse development of the fetus (e.g., in the case of thalidomide). Thus, unless information is available to the contrary for the chemical in question, it is prudent to assume that a single exposure to a teratogen may result in adverse developmental outcome. This being the case and since virtually all available reproductive/developmental studies are repeated exposure studies, a single daily dosage is therefore thought to be sufficient for the occurrence of developmental toxicity.
American Conference of Governmental Industrial Hygienists (ACGIH). Supplemental documentation. Cincinnati (OH): ACGIH; 1984. p.328-329.
Deichmann WM, Witherup S. Phenol studies VI. The acute and comparative toxicity of phenol and o-, m-, and p-cresols for experimental animals. J Pharmacol Exp Ther 1944;80:233-240.
Flickinger CW. The benzenediols: catechol, resorcinol and hydroquinone--a review of the industrial toxicology and current industrial exposure limits. Am Ind Hyg Assoc J 1976;37:596-606.
Piotrowski JK. Evaluation of exposure to phenol: absorption of phenol vapor in the lungs and through the skin and excretion of phenol in urine. Br J Ind Med 1971;28:172-178.
Ruth JH. Odor thresholds and irritation levels of several chemical substances: a review. Am Ind Hyg Assoc J 1986;47:A142-A151.