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DETAILED EVALUATION 4 DETAILED EVALUATION The remainder of this report details the subcommitteeâs review of NASAâs draft SWEGs documents. The page and line numbers cited correspond to those in NASAâs documents. MANGANESE The subcommittee reviewed NASAâs draft SWEGs document on manganese, presented by Dr. Raghupathy Ramanathan of Wyle Laboratories, and recommends the following revisions. The revised document should be re- evaluated by the subcommittee at its next meeting. Occurrence and Use NASA should add information on the concentrations of manganese found in water aboard Mir. Pharmacokinetics Because several of the key toxicity studies on manganese involve the use of bolus dosing (gavage) rather than continuous dosing (feed or water), a reasonable estimate is needed of the amount of manganese that is absorbed from feed or water compared to that absorbed after gavage. NASA should compare the available data on the absorption of manganese following the various oral dosing methods to determine whether the difference in absorption can be quantified. NASA presented an illustration of the absorption of manganese during the meeting that was not included in its document. That figure should be added to the SWEGs document. On page 3 (lines 26-27), NASA should specify the half-life reported in the Cotzias et al. (1968) study. Half- life data are also available in a study by Suzuki (1974). Another study that should be included is by Mena (1969), who compared the half-life of manganese between iron-deficient and iron-sufficient subjects and between miners exposed to manganese and subjects who were not exposed. NASA should also expand its discussion of studies that show two phases of elimination (slow and fast) of manganese (e.g., Mahoney and Small 1968; Britton and Cotzias 1966). On page 5 (lines 11-28), NASA provides a discussion of the influence of other minerals on manganese absorption. Because iron is identified as interfering with the absorption of manganese, NASA should specify whether astronauts are given iron supplements during spaceflight. On page 5 (line 22), NASA reports that calcium inhibited the absorption of manganese; however, NASA should review a study by Lassiter (1972), who reported that calcium enhanced the absorption of manganese. It should also be noted that ethanol has been shown to increase absorption of manganese (Schafer et al. 1974). Toxicity In several places in the SWEGs document on manganese (e.g., page 33, lines 4-6), NASA incorrectly states that neurotoxicity studies in rodents are not applicable to humans
DETAILED EVALUATION 5 because rodents lack melanin in the brain. Rodents do have melanin in the brain, but much less than is found in humans. Therefore, it is more appropriate to state that rodents are poor models of neurotoxicity rather than having no relevance to humans. More details are needed in the description of the 13-week study presented on pages 16-17 and summarized on page 35 (lines 2-11). Specifically, NASA should quantify the reported increases and decreases in the various hematological end points, such as hematocrit and lymphocyte counts, and specify whether the changes were significant. It would also be helpful if the actual doses administered were provided in the description of the study rather than in just the summary table. In the discussion of the neurological effects of manganese in humans (pages 23-25), the subcommittee recommends that more information be provided on environmental studies of exposure to manganese. For example, NASA should review a paper by Mergler (1999), who compares the evidence of parkinsonism found in communities that were exposed to manganese in drinking water in Greece, Japan, and China. NASA should expand upon that comparison by providing the details and quantitative data from those studies, such as the concentrations of exposure and the number of individuals in the population affected, and a comparative analysis of the findings. NASA should provide more details on the study of the effects of manganese on aggression, sexual behavior, and fertility in male rats (page 28, lines 7-20). In particular, the number of animals should be specified and mention should be made of whether the effects appear to be reversible. In the discussion of data on the inhalation of manganese, NASA should specify the forms of manganese that were studied. The details (e.g., test concentrations, exposure durations) of the genotoxicity studies on manganese (pages 19-21) should be provided in a table. NASA should use the genotoxicity table presented in the final SWEGs document on N-phenyl-beta-naphthylamine as an example. Dr. Gaulden should be contacted directly for advice in this area. Rationale The rationale section of the SWEGs document on manganese should include a discussion of the rate of absorption from dosing by gavage compared to dosing via feed or water (similar to the earlier recommendation). If possible, a quantitative assessment should be provided on the differences between routes and that information used in the derivation of the ACs for manganese. In the presentation of the guidance levels established by other organizations (page 29, Table 2), NASA should provide the U.S. Environmental Protection Agencyâs rationale for not establishing a maximum contaminant level for manganese in drinking water. On page 31 (lines 9-11), it is appropriate to recognize the difference in the manganese requirements between rodents and humans. However, that difference does not support the contention that humans might be more susceptible to manganese. NASA should reconsider its assessment that the Greek epidemiological study (presented on page 32, lines 7-18) cannot be used because of poor exposure data. The strength of that study is that it provides human data. Therefore, a better analysis of this study is needed to determine whether it is inadequate for deriving an AC. Dr. Halperin should be provided with a copy of the paper to assist in this assessment. On page 33 (lines 14-16), NASA discounts the use of a human study to derive a 1-day AC because only one individual was affected and the effects were serious. That rationale is weak, because it might be possible to consider the data in the context of other studies (i.e., the exposure in the study could represent an upper bound). NASA should provide a better
DETAILED EVALUATION 6 description and analysis of the study (as well as document the citation). From what little information is provided, it appears that a better reason for not using the study would be that the subject was already compromised (undergoing hemodialysis). NASAâs contention (page 33, lines 18-21) that LD50 data on manganese cannot be used to calculate ACs because long-term studies have been conducted at similar doses without significant mortality needs to be strengthened. The discrepancies observed between LD50 studies and longer-term studies should be discussed in the context of the route of administration (gavage vs. feed). The reason the LD50 data should not be used has to do with kinetics and dose-rate issues. There is a discrepancy in the data presented on page 33 (lines 26-32). It is reported that there was an increase in leukocytes and segmented neutrophils at the highest dose but in an earlier description of the study on page 17 and in the summary table on page 39, it is reported that those end points were decreased. In the discussion of the work of Joardar and Sharma (1990) on page 34, NASA expressed little confidence in the data on increased sperm head abnormalities because no histological effects were found in the testes of rats from another study. The subcommittee finds this argument to be weak. There are other aspects of the Joardar study that might make it inadequate for determining an AC for manganese. However, not enough details were provided in the document (either in the Rationale section or the Reproductive Toxicity section) to make a complete evaluation of the study. NASA should provide the details of the Joardar study in the toxicity section on page 27 and a critical analysis of the data. Specifically, it would be of interest to know how sperm head abnormalities were determined and the time point during spermatogenesis when the abnormalities were measured. In a brief review of the study, the subcommittee noted that the incidence of sperm head abnormalities appears to be low in the control mice. NASA should review data on background concentrations of sperm head abnormalities in Swiss albino mice to see if this is the case. NASA should also discuss and analyze the clastogenicity data reported in the Joardar study. It might be appropriate to derive an AC based on that end point. NASA should also review the Joardar data in the context of the differences in absorption by gavage compared to feed or drinking water exposure. During the subcommittee meeting, NASA presented examples of how it used the BMD approach to derive 1000-day ACs for manganese. The subcommittee recommends that information be added to the document so that it can evaluate the data more carefully. Of particular interest is the determination of the BMDL01 based on the follicular hyperplasia and follicular dilation reported in the NTP (1993) study. References The International Programme on Chemical Safety (1981) has a review document on manganese that should be reviewed for supplemental information (e.g., effects on the thyroid, cardiovascular system, and immune system; neurotoxicity studies with primates) and cited in the report. That report also provides a set of daily requirements for manganese, which should be referenced in the SWEGs document. Editorial Comments On page 2 (lines 13-14), it is stated that the highest concentration of manganese found in nuts and grains is 40 ppm, but a range of 18-46 ppm is provided in the same sentence. On page 3 (lines 31-ff), phytate should be defined.
DETAILED EVALUATION 7 Page 30 (line 8) refers to nickel rather than manganese. 2-MERCAPTOBENZOTHIAZOLE (MBT) The subcommittee reviewed NASAâs draft SWEGs document on MBT, presented by Dr. Hector Garcia of Wyle Laboratories, and recommends the following revisions. The revised document should be re-evaluated by the subcommittee at its next meeting. Physical and Chemical Properties The octanol-to-water partition coefficient for MBT should be specified to support the statement on page 2 (line 15) that it is high. Occurrence and Use The data presented in Table 1 (page 2) should be verified, because they indicate that the mean concentration of MBT is equivalent to the highest concentration detected. Pharmacokinetics and Metabolism On page 3 (line 28), the âsulfonic acid derivative of MBTâ should be specified. NASA should add studies of compounds related to MBT that could contribute to the understanding of the conjugated metabolites of MBT. For example, there are several metabolism studies of chemicals, such as the 2-thiobenzothiazoles, in which MBT is an intermediate metabolite (e.g., Fukuoka and Tanaka 1987; Fukuoka et al. 1995). The dermal LD50 data on MBT presented on page 4 (line 10) indicates that MBT is absorbed through the skin. More quantitative information about the dermal absorption of MBT from this study and other dermal studies should be added to the absorption section of the SWEGs document. Toxicity A better assessment of the contact sensitizing potential of MBT is needed. For example, clarification is needed of the description of manganese as a âmoderateâ sensitizer (page 4, line 47). NASA should include a discussion of (1) what percentage of the general population has contact allergies to MBT, (2) how MBT compares in potency with other contact sensitizers, such as nickel and diisocyanate, and (3) data on reactions among MBT-sensitive individuals exposed to MBT orally. NASA should review the available data and contact individuals who have done research in this area (e.g., Emmett et al. 1994). On page 5 (line 43), the significance of the presence of interstitial cell infiltration in the kidney of mice exposed to MBT (Ogawa et al. 1989) is unclear. NASA should contact subcommittee member Dr. Bernard Wagner, who was unable to attend the meeting, for an assessment of the significance of this finding. In Table 3 (page 7), which presents tumor incidence in rats exposed to MBT, actual data (e.g., number of animals with and without tumors) and statistical comparisons should be included rather than simply listing the incidence rate of tumors. It also should be specified
DETAILED EVALUATION 8 whether standard-error or standard-deviation information is being presented in the column on historical controls. NASA should provide a more detailed description and evaluation of the studies on reproductive toxicity and developmental and fetal toxicity. In particular, NASA should specify the route of exposure, number of animals used, doses, and end points evaluated. A discussion of the nephrotoxicity observed in rats exposed to MBT in the NTP (1988) study should be added to the SWEGs document, particularly since it might support the findings in the mouse reported by Ogawa et al. (1989). NASA should evaluate the NTP data to determine whether an AC can be calculated on the basis of the nephrotoxicity data. Better descriptions and evaluations of the epidemiological studies presented on page 6 (lines 17-30) are needed to critically evaluate them. For example, the cancer standard mortality ratios and confidence intervals should be provided. A critical analysis of the data are particularly important if the studies are to be used to support NASAâs decision not to calculate an AC based upon tumorigenesis in laboratory animals. The details (e.g., test concentrations, exposure durations) of the genotoxicity studies on MBT (pages 7-8) should be provided in a table. NASA should use the genotoxicity table presented in the final SWEGs document on N-phenyl-beta-naphthylamine as an example. Dr. Gaulden should be contacted directly for advice in this area. Rationale The rationale for why NASA did not use the tumorigenesis data in laboratory animals to calculate an AC should be expanded. It appears that the main reason for why the tumor data cannot be used to derive an AC (page 12, lines 10-13) is the lack of a good dose response. NASA should further support its decision with the results of the epidemiological studies, which did not show an increased incidence of cancer among workers exposed to MBT. NASA should review the epidemiological studies to determine how the investigators considered the animal data within the context of their own findings. Because MBT is very insoluble in water, a statement should be added to NASAâs document explaining why it is necessary to set a drinking-water guideline for that contaminant. Editorial Comments The reference for the NTP (1988) study should be added to the report. SILVER The subcommittee reviewed NASAâs draft SWEGs document on silver, presented by Dr. Raghupathy Ramanathan of Wyle Laboratories, and concluded that the document is ready to be finalized once the following changes are made. Toxicity On page 13 (line 32), it is contradictory to state that there were no signs of overt toxicity when the ocular membranes of rats are described as âcompletely black.â
DETAILED EVALUATION 9 Clarification is also needed of the description of the study by Walker (1971). Page 14 (lines 6-8) indicates that a dose of 130 mg/kg-day was administered to rats in drinking water, but a dose of 65 mg/kg-day is identified as the NOAEL for the study. Rationale On page 20 (line 24), NASA contends that a factor of 10 should be used to account for differences in silver absorption between rodents and humans. NASA should verify that absorption by rats and mice are similar enough to support this contention. During the meeting, NASA informed the subcommittee that it would justify its decision not to use the swine study by Van Vleet (1976) to calculate a 10-day AC by noting that the exposed groups were tested at different times, and that the high-dose animals were older and larger than the low-dose animals and, therefore, had greater feed intake (silver ingestion) and uptake because of increased body size. An assumption cannot be made that the food-consumption rate per kilogram of body weight in adult animals is higher than that for younger animals. Because there are no data to support this contention, the subcommittee believes this is an inadequate justification. It would be better to justify the lack of confidence in the data by noting the small number of test animals and by noting that the NOAEL of 52 mg/kg-day is only slightly lower (a factor of 2.5 less) than the dose that killed 75% of the test animals (3 of 4 swine). References must be added to support the statement on page 23 (lines 26-27) that rats are more sensitive to neurotoxicity than humans. On page 25 (line 15), NASA uses an assumption that the mean absorption of silver in man is 10%. That absorption rate is lower than the 20% rate that is reported in the table on page 4. NASA should verify that the correct rate was used in the calculation of the 1000-day AC. ZINC AND ITS SALTS The subcommittee reviewed NASAâs draft SWEGs document on zinc and its salts, presented by Dr. Raghupathy Ramanathan of Wyle Laboratories, and recommends the following changes. The revised document can be finalized after Drs. Halperin, Faustman, Feigley, and Kodell have reviewed and approved it. Use and Occurrence If available, NASA should provide the concentration range at which zinc has been detected in spacecraft water. Pharmacokinetics and Metabolism On page 7 (lines 21-22), NASA should discuss whether copper has an effect on the absorption of zinc. Because the two metals are described as being âantagonists,â it is likely that the inhibition of absorption applies to both compounds.
DETAILED EVALUATION 10 Rationale NASA should follow-up on two recommendations the subcommittee made at its last meeting. First, NASA should not use a decrease in high density lipoproteins as a toxicity end point for calculating ACs for zinc. Second, a full description and evaluation of a 22-week study in rabbits (Bentley and Grubb 1991) should be provided. On page 29 (lines 35-36), NASA contends that this study was not relevant for calculating ACs because the study was done in rabbits, but no substantiation was provided to support this conclusion. Furthermore, no details or discussion of the study is provided in the Toxicity section. The data must be fully described and analyzed and, if appropriate, be used to calculate 100-day and 1000-day ACs. If the data are not used, a scientifically valid explanation must be provided. On page 24 (line 14-15), NASA made a decision to use an uncertainty factor of 3 instead of 10 to extrapolate from a LOAEL to a NOAEL in its derivation of the ACs for zinc. The rationale provided to support this decision implies that the selected toxicity end points for zinc do not pose significant health effects. The subcommittee believes it is inappropriate to make this generalization for all the ACs. Each case must be considered and justified on an individual basis in the text, and a notation should be added to Table 4. Furthermore, it is inappropriate to lower the uncertainty factor used to extrapolate from a LOAEL to a NOAEL on the basis that the end point in question is not a serious health concern. On page 24 (lines 19-20), NASA should specify the hematological effects associated with space flight that warrant the use of an additional space-flight factor when that type of end point is used to calculate an AC. The calculated 1-day SWEG (page 26, line 4; page 31, Table 4, row 1) should be rounded down to 12 mg/L. In the discussion of how the 10-day AC was calculated on the basis of the Chandra (1984) study, NASA should consolidate its discussion of the results and clearly specify the types of lipid and immunological effects observed. Although the LOAEL was the same for both types of effects, it seems that the immunological effects would be more important than the lipid effects. If that is the case, NASA should specify that as the end point of concern and provide a justification for it. The subcommittee also recommends that NASA reconsider its use of an uncertainty factor of 3 to extrapolate from a LOAEL to a NOAEL (as discussed earlier). On page 27 (lines 18-33), NASA should expand its rationale for deriving an AC based on the Yadrick et al. (1989) study. First, the significance of decreased erythrocyte superoxide dismutase (ESOD) on human health should be clarified. Second, it should be recognized that the LOAELs identified for a 10-week exposure are close to the NOAELs identified at 6 weeks. NASA should explore the various ways of using the data and the uncertainties associated with each of the methods. For example, if a LOAEL is used, NASA should take into consideration that a default uncertainty factor of 10 to extrapolate for a LOAEL to NOAEL is likely to be overly conservative. On the other hand, it should be considered whether it is scientifically justified to use a NOAEL on the basis of 6-week data when there are data at 10 weeks that show effects. The subcommittee recommends that NASA presents the various ways the data can be handled so that the subcommittee can make a judgement about the most appropriate way of calculating a 100-day AC. In its calculation of a 100-day AC for zinc on the basis of spermatogenic effects (page 29, lines 1-18), NASA should discuss the significance of the effects on sperm chromatin and changes in cell types. Also, NASA selected an uncertainty factor of 3 to extrapolate from a LOAEL to a NOAEL. However, it has not adequately justified the use a factor lower than 10 for this extrapolation, particularly in light of its judgement (page 29, lines 7-8) that the effect was a âserious adverse effect.â A better rationale should be provided or a factor of 10 should be used.
DETAILED EVALUATION 11 NASA should verify that it has conducted and documented all of its calculations properly. For example, there is an error on page 30 (line 25); a time factor of 1000/180 is reported to be 11.11 rather than 5.55. NASA should add a brief discussion that the ACs are close to the recommended daily allowances for zinc. Also, a footnote should be added to Table 4 that the SWEGs are close to levels found in vitamins. Editorial Comments The data table on page 27 should indicate whether the asterisk (*) signifies a statistically significant difference from controls. BARIUM AND ITS SALTS The subcommittee reviewed NASAâs draft SWEGs document on barium and its salts and NASAâs response to Interim Report #3 on Spacecraft Water Exposure Guidelines (NRC 2000b), presented by Dr. Raghupathy Ramanathan of Wyle Laboratories, and recommends the following revisions. The revised document should be re- evaluated by the subcommittee at its next meeting. Toxicity NASA should add to its toxicity summary a review of the work of Blakeborough et al. (1997) and Roeske et al. (1975), who investigated the incidence of cardiac arrhythmias following radiological use of barium. A determination should be made of whether cardiac arrhythmias are an end point of concern for astronauts exposed to barium. Although it is unlikely that the studies can be used to derive an AC for barium, it is important for NASA to consider the data and to include a review of the studies in its toxicity discussion. On page 6 (lines 7-14), a discussion of the mortality data from the Brenniman and Levy (1985) study should be added. It is not necessary to use that data as an end point for deriving an AC, but the data should be provided as part of the evaluation of the study. The description of the study by Brenniman and Levy (1985) on page 10 (lines 20-30), should be revised to make it clear that the investigators compared data between different communities and not between men and women. Also, the phrase âinfluence of duration of exposureâ (lines 27-28) should be deleted, because it was not used to correct the data. On page 12 (line 26ff), NASA should provide a discussion of whether the proteinuria observed in the Schroeder and Mitchener (1975a, b) studies is a significant finding that has implications for human health. It would be of interest to know whether NTP (1994) characterized this study in its report. If proteinuria is not considered biologically important, then it should not be used to derive an AC. NASA informed the subcommittee of its intention to add more details on the genotoxicity assays of barium to its document before it is finalized. NASA should create a table similar to the one used in the final SWEGs document on N-phenyl-beta-naphthylamine. The table should be completed and sent to Dr. Gaulden for her approval before the next meeting.
DETAILED EVALUATION 12 Rationale Because oral doses of barium are routinely used in radiological examinations, the subcommittee believes the typical doses used in such exams will be directly relevant for determining a 1-day SWEG for barium. Dr. Gaulden will provide NASA with information on the typical doses of barium that are used in hospitals. That information should be presented in the SWEGs document, and a discussion of the literature pertaining to any adverse effects associated with oral administration of barium for radiological purposes added. If such data are not available, then an approximate NOAEL for a 1-day AC could be based on the average dose of barium administered to patients during routine clinical procedures. NASA should not use hypertension as an end point for calculating ACs for barium, because no convincing data have been presented for barium-induced hypertension in humans. A discussion describing why this end point is not used, despite several examples in the literature of hypertension in experimental animals, should be incorporated into the rationale section of the revised document. NASA should also follow-up on its preliminary investigation of whether differences in renal physiology between rats and humans (i.e., vascular shunt) can be used to further support the decision not to use hypertension as a basis for deriving ACs for barium. NASA should provide Dr. Wagner with a discussion of its findings in this area for his comments. On page 20 (line 30), it is unnecessary to apply a space flight factor of 3 for a 1-day AC because of gastrointestinal inflammation. Some intestinal irritation is acceptable for setting a 1-day AC (an exposure guidance level used for emergency situations), provided the effects are reversible and do not compromise crew performance. Thus, the 1-day AC on the basis of gastrointestinal inflammation should be 165 mg/L. During the meeting, NASA presented some BMD calculations conducted using the barium data. It is important to include all of those calculations (whether or not they are used to derive an AC) into the SWEGs documents, so that it is clear that NASA considered using the BMD approach in its calculations. There are two cases in which the subcommittee believes it is appropriate to use the BMD approach. First, the subcommittee recommends that NASA use the BMDL01 of 32.5 mg/kg-day on the basis of neurobehavioral effects observed in rats during a 13-week study (NTP 1994) to calculate a 100-day AC. This calculation should replace the one presented in Table 4 (page 27, line 8). Second, NASA should use the BMDL01 calculated on the basis of renal nephropathy observed in rats (NTP 1994) to calculate a 1000-day AC. That calculation should also be added to Table 4 (page 27). On page 24 (lines 38-41) and in Table 4 (page 27), NASA should not use the Schroeder and Michener (1975a, b) studies as a basis for calculating a 1000-day AC, because no barium-related effects were observed in the studies. Editorial Comments The sentence on page 3 (lines 26-27) should be deleted because it is redundant with the preceding sentence. NICKEL The subcommittee reviewed NASAâs draft SWEGs document on nickel and its responses to Interim Report #3 on Spacecraft Water Exposure Guidelines (NRC 2000b), presented by Dr. Raghupathy Ramanathan of Wyle Laboratories, and recommends the
DETAILED EVALUATION 13 following revisions. The revised document should be re-evaluated by the subcommittee at its next meeting. Pharmacokinetics On pages 3-4, a discussion should be added of the potential effects of nickel on iron absorption. Specifically, consideration should be given to whether chronic ingestion of nickel compounds in water might induce iron deficiency in astronauts by impairing gastrointestinal absorption of iron. A few relevant papers include Nielsen et al. (1979), Nielson (1980), Schafer and Forth (1983), Tallkvist et al. (1994), Tallkvist and Tjalve (1998). Rationale The primary issue the subcommittee will consider at its next meeting is whether the SWEGs for nickel should include an adjustment to account for its known contact sensitization. Because nickel sensitization is a fairly common finding in the general population, it might be necessary to consider this in the derivation of the ACs. Alternatively, it might not be scientifically justified to account for such an effect if the basis of the AC is not related to contact sensitization. To aid the subcommittee, NASA should include a discussion in its document of how EPA considered the issue of nickel contact sensitivity in its establishment of the reference dose for nickel. In the calculation of the 1-day AC (page 25, line 26), NASA has not justified the use of a âdefaultâ factor of 3 in addition to a factor of 10 to extrapolate from a LOAEL to a NOAEL. The subcommittee believes that a factor of 10 alone is adequate for the adjustment because the range of exposure to nickel was reasonably small (7-36 mg/kg), the methods used to determine the concentrations appeared to be adequate, and the observed effects (giddiness, weariness, headache) are not severe health effects. The 1-day AC should be recalculated accordingly. There is an error in the calculation of the 100-day AC on the basis of granulocyte macrophage colony forming units (page 30, Table beginning on line 1). The AC based on the LOAEL/NOAEL method should be 1.7 mg/L and not 2.3 mg/L. The correct 100-day AC value is reported in Table 6 (page 35), but no explanation is provided for how the same data were used to also derive a 10-day AC of 2.3. Editorial Comments The references for the Onkelinx et al. (1973) and the OâFlaherty (1998) studies should be added to the document. DI(2-ETHYLHEXYL) PHTHALATE (DEHP) The subcommittee reviewed NASAâs draft SWEGs document on DEHP and its responses to suggestions from Interim Report #3 on Spacecraft Water Exposure Guidelines (NRC 2000b), presented by Dr. John James of NASA, and recommends the following revisions. The revised document should be re-evaluated by the subcommittee at its next meeting.
DETAILED EVALUATION 14 Occurrence and Use Because DEHP is used in plastics that encase food products, information about the potential leaching of DEHP into the food of astronauts should be added. Toxicokinetics In the figure illustrating the metabolism of DEHP (presented as the facing page of page 4), NASA should include the common names for the major metabolites of DEHP. NASA should add the material it presented during the meeting on the low and high dose kinetics of phthalates across animal species to its SWEGs document. It should also include the two figures presented from the Holden and Tugwood (1999) paper. Toxicity On page 9 (lines 9-37), the subcommittee disagrees with NASA that Sertoli cell vacuolization should be considered an adaptive change and not an adverse effect. Sertoli cell vacuolization has been observed in other studies of DEHP and is considered by reproductive toxicologists to be an indicator of toxicity. Dr. Faustman will share information she has on the topic with NASA to support this conclusion. Given the revised conclusion, the NOAEL for the study by Poon et al. (1997) on the basis of Sertoli cell vacuolization is 4 mg/kg-day and not 38 mg/kg-day. In Table 1a (page 9), which presents data on histological changes found in the testes of male rats fed DEHP, it should be clarified whether data on severity and dispersion are considered separately or together; scoring information is presented in the footnote of the table, but it is unclear how the data were handled. On page 9 (lines 42-43), the subcommittee believes the statement that marmosets are better models than rats for reproductive effects should be tempered, because there is evidence that marmosets are not as responsive as other primates. Dr. Faustman will provide NASA with the appropriate references to cite. The details (e.g., test concentrations, exposure durations) of the genotoxicity studies on DEHP (pages 19-21) should be provided in a table. NASA should use the genotoxicity table presented in the final SWEGs document on N-phenyl-beta-naphthylamine as an example. Dr. Gaulden may be contacted directly for advice in this area. Rationale To be consistent with the recommended guidelines for calculating SWEGs when the BMD approach is used (see NRC 2000), the BMDL01 rather than the BMD01 should be used as the starting point for the calculations. In its modeling of the chronic kidney inflammation data from Kluwe et al. (1982), it would be of interest to know whether NASA also used a log logistic model to model the data. If possible, the BMD approach should be used on the incidence data of Sertoli cell vacuolization in rats (Poon et al. 1997), and a discussion of the severity of the responses should be included. A rationale should be provided if it is determined that the data cannot be used in this way. The subcommittee recommends that the data on red blood cell counts in the David et al. (2000) study not be used as a basis for calculating an AC, because the observed effects were
DETAILED EVALUATION 15 not statistically or biologically significant. However, it appears that the data on aspermiogenesis from the same study can be handled using the BMD approach. NASA should use a variety of models to model the data and determine the p values for each of the models. Drs. Kodell and Faustman should be consulted in finding the best approach for determining the BMDL01. DI-N-BUTYL PHTHALATE (DBP) The subcommittee reviewed NASAâs draft SWEGs document on DBP, presented by Dr. John James of NASA, and recommends the following changes. The revised document can be finalized after Drs. Carlson, Faustman, and Kodell have reviewed and approved it. Occurrence and Use Because DBP is used in plastics that encase food products, information about the potential leaching of DBP into the food of astronauts should be added. Toxicity In its discussion of the reproductive toxicity of DBP, NASA should include a discussion of the anti- androgenicity of DBP, which is the likely mechanism for testicular effects in rodents. Rationale NASA must revise all of its AC calculations for DBP that use a BMD, because the BMDL01 rather than the BMD01 should be used as the starting point for calculating ACs. To aid the general reader, NASA should include the following explanation of the BMDL01 as a footnote to Table 4 (page 20): âBMDL01 is the lower statistical bound on an exposure level corresponding to an increase of 1% in the probability of an adverse response. For continuous data, the range for adverse effects is considered to be 0.5%, which corresponds to 2.58 standard deviations from the mean response of unexposed individuals. (See NRC 2000a).â This footnote should also be used in other SWEGs documents when appropriate. On page 10, the subcommittee agrees with NASAâs use of sperm count rather than acid phosphatase activity as an end point to calculate an AC; but it should be acknowledged that the enzyme changes could be markers of testicular effects.
