4
Reproductive and Developmental Effects

The Environmental Protection Agency (EPA) draft Integrated Risk Information System (IRIS) assessment describes the key animal developmental-toxicity and reproductive-toxicity studies of tetrachloroethylene in Section 4.7.2 and provides useful summaries of the study results in its Tables 4-8 and 4-10. In evaluating the studies described by EPA, the committee applied several criteria to determine whether there is sufficient evidence to identify tetrachloroethylene as a reproductive or developmental toxicant in animals and to identify a reference concentration based on reproductive or developmental end points. The criteria included consideration of identification of adverse effects that were not confounded by excessive maternal toxicity, use of multiple experimental exposures, identification of a no-observed-adverse-effect level (NOAEL), and conformity with current regulatory testing guidelines.

The committee agrees with the NOAEL of 100 ppm based on the study by Tinston (1994). EPA’a derivation of a comparative reference value (RfV) based on reproductive or developmental toxicity is an important addition to the toxicologic information on tetrachloroethylene and will be helpful in assessing potential health risks related to these end points. However, EPA’s rationale for selecting the Tinston (1994) study instead of the Carney et al. (2006) study for the benchmark dose analysis and derivation of the RfV is not presented in the document and therefore is unclear. A major criticism of Section 4.7.2 has to do with the general lack of transparency regarding the critical analysis that EPA conducted of the studies described. The strengths and limitations of individual studies are not adequately discussed, and evaluations of reported maternal toxicity and comparisons of studies that yielded supporting or conflicting evidence of developmental or reproductive toxicity are not adequate. As a result, the reader cannot readily conclude that EPA had sufficient data for a risk assessment. Furthermore, the scientific basis for considering some studies and not others for derivation of a comparative RfV based on reproductive or developmental toxicity is not apparent. EPA does not state whether the experimental animal evidence of tetrachloroethylene-induced developmental toxicity and reproductive



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4 Reproductive and Developmental Effects The Environmental Protection Agency (EPA) draft Integrated Risk Infor- mation System (IRIS) assessment describes the key animal developmental- toxicity and reproductive-toxicity studies of tetrachloroethylene in Section 4.7.2 and provides useful summaries of the study results in its Tables 4-8 and 4-10. In evaluating the studies described by EPA, the committee applied several criteria to determine whether there is sufficient evidence to identify tetrachloroethylene as a reproductive or developmental toxicant in animals and to identify a refer- ence concentration based on reproductive or developmental end points. The cri- teria included consideration of identification of adverse effects that were not confounded by excessive maternal toxicity, use of multiple experimental expo- sures, identification of a no-observed-adverse-effect level (NOAEL), and con- formity with current regulatory testing guidelines. The committee agrees with the NOAEL of 100 ppm based on the study by Tinston (1994). EPA’a derivation of a comparative reference value (RfV) based on reproductive or developmental toxicity is an important addition to the toxi- cologic information on tetrachloroethylene and will be helpful in assessing po- tential health risks related to these end points. However, EPA’s rationale for selecting the Tinston (1994) study instead of the Carney et al. (2006) study for the benchmark dose analysis and derivation of the RfV is not presented in the document and therefore is unclear. A major criticism of Section 4.7.2 has to do with the general lack of transparency regarding the critical analysis that EPA conducted of the studies described. The strengths and limitations of individual studies are not adequately discussed, and evaluations of reported maternal toxic- ity and comparisons of studies that yielded supporting or conflicting evidence of developmental or reproductive toxicity are not adequate. As a result, the reader cannot readily conclude that EPA had sufficient data for a risk assessment. Fur- thermore, the scientific basis for considering some studies and not others for derivation of a comparative RfV based on reproductive or developmental toxic- ity is not apparent. EPA does not state whether the experimental animal evi- dence of tetrachloroethylene-induced developmental toxicity and reproductive 42

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43 Reproductive and Developmental Effects toxicity is sufficient or insufficient on the basis of criteria in its risk-assessment guidelines. Some of the specific deficiencies in Section 4.7.2 are described be- low. LIMITATIONS OF THE DATABASE Information analogous to that on page 4-124 of the draft IRIS assessment, which discusses general limitations of the human reproductive-toxicity and de- velopmental-toxicity studies, would be useful. It would provide a context for the descriptions of individual studies and would be helpful in characterizing the animal developmental-toxicity and reproductive-toxicity data available for haz- ard identification and dose-response evaluation. For example, only two studies of the reproductive toxicity of tetrachloroethylene are described, and many of the developmental-toxicity studies described have limitations. The limitations include use of a single exposure level, insufficient study details, excessive ma- ternal toxicity, and lack of conformity with current EPA and Organisation for Economic Co-operation and Development (OECD) regulatory testing guidelines because of when the studies were conducted. COMBINED DISCUSSION OF REPRODUCTIVE AND DEVELOPMENTAL TOXICITY EPA discusses the evidence on reproductive toxicity and developmental toxicity together. Without a separate discussion of each, it is difficult to identify conflicting data and data gaps and to assess whether there is sufficient evidence of toxicity for each end point according to the criteria in the EPA (1991, 1996) guidelines. The sequence or order in which the studies are described in Section 4.7.2 complicates the issue. The two studies that provide specific information on the reproductive toxicity of tetrachloroethylene, Tinston (1994) and Beliles et al. (1980), are not discussed sequentially. The end-point-specific evidence from the well-conducted Tinston (1994) reproduction study and the Carney et al. (2006) developmental-toxicity study is either not stated or not emphasized by EPA. For example, EPA does not conclude from the Tinston (1994) two-generation repro- duction study that tetrachloroethylene had no significant effect on reproductive performance or fertility in rats at up to 1,000 ppm. The results of the Beliles et al. (1980) study, which showed that tetrachloroethylene at 500 ppm had no sig- nificant effect on the sperm of rats, are consistent with the adverse effect on fer- tility in the Tinston study, but the relationship of this finding to the Tinston (1994) study is not discussed. The Summary on page 4-134 does not mention the results of the Carney et al. (2006) developmental study, which showed that tet- rachloroethylene at 249 ppm, in the absence of maternal toxicity, can produce developmental toxicity in rats (reduced fetal and placental weights and incom- plete ossification of thoracic vertebral centra).

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44 Review of the EPA’s Draft IRIS Assessment of Tetrachloroethylene EVALUATION OF THE RELATIONSHIP OF MATERNAL AND DEVELOPMENTAL TOXICITY The EPA risk-assessment guidelines (EPA 1991, p. 18) state: “Since the final risk assessment not only takes into account the potential hazard of an agent, but also the nature of the dose-response relationship, it is important that the rela- tionship of maternal and developmental toxicity be evaluated and described.” It is not clear whether EPA evaluated the range of maternal-toxicity data (mild to severe effects) that are reported in the studies described, inasmuch as interpreta- tion of the data with regard to the developmental toxicity of tetrachloroethylene is not presented. For example, in the Schwetz et al. (1975) study, tetrachloro- ethylene produced a statistically significant increase in resorptions and mild, statistically significant maternal toxicity (4-5% reductions in mean maternal body weight compared with controls) in rats. Food consumption and liver weights were not affected by tetrachloroethylene exposure. Maternal toxicity is listed in the EPA draft’s Table 4-8 as an “Effect,” but there is no discussion of its relationship to the increased resorptions. According to the EPA risk- assessment guidelines, the increased resorptions in the Schwetz et al. (1975) study represent tetrachloroethylene-induced developmental toxicity in that they were produced at doses that caused minimal maternal toxicity. Maternal toxicity (decreased body weight gain and increased liver weight and serum enzyme ac- tivities) at tetrachloroethylene concentrations of 221, 664, and 1,254 ppm is also listed as an “Effect” in Table 4-8 for the Szakmary et al. (1997) study. EPA does not point out that the excessive maternal toxicity at 664 and 1,254 ppm (de- creases of 37% and 40% in maternal body-weight gain, respectively, compared with 13% at 221 ppm) makes the developmental effects (such as skeletal retar- dation and decreased fetal weight) difficult to interpret and of limited value on the basis of its risk-assessment guidelines. STUDY STRENGTHS AND LIMITATIONS AND CONSISTENCY OF RESULTS Section 4.7.2 of the EPA draft does not identify the studies that are scien- tifically strong and the studies that are weak. Supportive and conflicting studies in the database also are not adequately identified. For example, EPA does not explain why confidence in the Tinston (1994) and Carney et al. (2006) studies should be higher than in the other studies described. In addition to being well conducted, both Tinston and Carney et al. have multiple experimental expo- sures, report effects associated with lower exposures that are not confounded by excessive maternal toxicity, and identify NOAELs. As indicated on page 5-4 of the draft, EPA considered those studies supportive of a point of departure to derive an RfV based on some of these strengths. EPA (2008, p. 4-137) indicates that reduced birth weight was found in five studies but does not discuss the con- sistent finding of tetrachloroethylene developmental toxicity at similar concen-

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45 Reproductive and Developmental Effects trations in Tinston (300 ppm), Carney et al. at (249 ppm), Schwetz et al. (300 ppm), and Szakmary et al. (221 ppm) or the conflicting finding of no develop- mental toxicity at 500 ppm in the Hardin et al. (1981) study. The limitations of Hardin et al. (single exposure level and lack of minimal maternal toxicity), Schwetz et al. (single exposure level), Nelson et al. (1979) (insufficient study details), and Szakmary et al. (lack of dose-response relationship because of ex- cessive maternal toxicity at higher exposure levels) also are not discussed. In addition, the studies that do not conform to EPA and OECD regulatory testing guidelines are not identified. STRENGTH OF EVIDENCE The summary of the data on the developmental toxicity of tetrachloro- ethylene from selected studies is not particularly helpful, because EPA did not present its evaluation of the information and the basis for citing particular stud- ies and study results is unclear. For example, EPA cites limited developmental- toxicity studies, such as Szakmary et al. (1997) and Schwetz et al. (1975), but does not cite Carney et al. (2006), the strongest one. EPA’s reason for citing tetrachloroethylene-induced behavioral changes as evidence of developmental toxicity in the summary also is not clear, and the citation does not seem to be supported by the data. Tetrachloroethylene’s effects at 1,000 ppm in the Tinston (1994) study are described on page 4-131 as central nervous system (CNS) de- pression and in Table 4-9 as behavioral effects. CNS depression appears to be more accurate on the basis of the symptoms described. The behavioral effects reported by Szakmary et al. (1997) are confounded by excessive maternal toxic- ity, and tetrachloroethylene had minimal effects on the behavior of rats in the study by Nelson et al. (1979). EPA provides no summary information on the reproductive toxicity of tetrachloroethylene even though data are available from a well-conducted two-generation reproduction study (Tinston 1994). Stating whether tetrachloroethylene can be identified as a developmental toxicant or a reproductive toxicant according to the criteria in the EPA developmental- toxicity risk-assessment guidelines (EPA 1991) and reproductive-toxicity risk- assessment guidelines (EPA 1996) would be helpful to risk managers and others and would help to identify data gaps. For example, there is sufficient evidence to identify tetrachloroethylene as a developmental toxicant in experimental animals on the basis of the results of Carney et al. (2006) and Tinston (1994). That conclusion is consistent with the developmental-toxicity risk-assessment guidelines (EPA 1996, p. 40), which state: “The minimum evidence necessary to judge that a potential hazard exists generally would be data demonstrating an adverse developmental effect in a single, appropriate, well-conducted study in a single experimental animal spe- cies.” There is insufficient evidence to indicate that tetrachloroethylene does not cause reproductive toxicity in experimental animals on the basis of the negative findings on reproductive performance and fertility in Tinston. That conclusion is

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46 Review of the EPA’s Draft IRIS Assessment of Tetrachloroethylene consistent with the reproductive-toxicity risk-assessment guidelines (EPA 1991, p. 72), which state: “The minimum evidence needed to determine that a potential hazard does not exist would include data on an adequate array of endpoints from more than one study with two species that showed no adverse reproductive ef- fects at doses that were minimally toxic in terms of inducing an adverse effect. Information on pharmacokinetics, mechanisms, or known properties of the chemical class may also strengthen the evidence.” ATTRIBUTING DEVELOPMENTAL TOXICITY TO TRICHLOROACETIC ACID EPA’s speculation in Section 4.7.4 of the draft that trichloroacetic acid (TCA) is the causative agent in the developmental toxicity of tetrachloroethyl- ene does not seem scientifically sound, and the discussion is not balanced. The available scientific data appear to contradict EPA’s speculation. In the studies by Schwetz et al. (1975) and Carney et al. (2006), trichloroethylene (in contrast with tetrachloroethylene) did not cause developmental toxicity even though higher concentrations of TCA should have been produced from trichloroethyl- ene than from tetrachloroethylene. In addition, tetrachloroethylene and TCA produce different types of developmental toxicity. Oral administration of TCA has consistently produced cardiac malformations in rats (Smith et al. 1989; Johnson et al. 1998). Dichloroacetic acid (DCA) also produces cardiac malfor- mations when administered orally to rats (Smith et al. 1992; Epstein et al. 1992). The malformations produced by TCA and DCA are consistent with the terato- genic potential of other weak acids, such as valproic acid and ethylhexanoic acid (Scott et al. 1994), but are not consistent with tetrachloroethylene-induced de- velopmental toxicity. The developmental toxicity produced by tetrachloroethyl- ene did not include cardiac malformations in any of the studies described by EPA in Section 4.7.2. EPA’s discussion of the evidence supporting TCA as the causative agent in tetrachloroethylene developmental toxicity is not balanced. EPA did not comment on the relatively high concentrations of TCA required to cause developmental toxicity compared with the concentration expected to result from metabolism of tetrachloroethylene in vivo or on whether this could account for the difference in the type of developmental effects that result from tetra- chloroethylene exposure. The lack of information on the availability of metabo- lized TCA to the developing fetus and the potential differences related to oral vs inhalation exposure in the TCA and tetrachloroethylene studies, respectively, also were not addressed. EPIDEMIOLOGIC STUDIES Few epidemiologic studies bear on possible associations between exposure to tetrachloroethylene and the specific adverse reproductive outcomes consid- ered. Most of the available studies have serious methodologic limitations and so

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47 Reproductive and Developmental Effects are not particularly informative as to the potential adverse reproductive effects of tetrachloroethylene exposure. Challenges that commonly confront investiga- tors conducting epidemiologic studies of environmental determinants of repro- ductive health were evident in the available literature, specifically, standard case definitions, systematic ascertainment of end points, correct classification of ex- posure with respect to timing of pregnancy, and specificity of exposure to tetra- chloroethylene. The draft IRIS assessment considered the evidence on reproductive effects of tetrachloroethylene to be limited but cited spontaneous abortion as the out- come for which the evidence of an association with tetrachloroethylene was strongest on the basis of results in three papers (Kyyronen et al. 1989; Olsen et al. 1990; Doyle et al. 1997). In general, the committee agrees with EPA’s asses- sement but takes a cautious view of inferences about the reproductive effects of tetrachloroethylene. The committee considered the work by Doyle et al. (1997) and Kyyronen et al. (1989) to be the most methodologically sound because they were based on cohorts of employed women about whom there was some infor- mation on tetrachloroethylen exposure and there was adequate evidence that the spontaneous abortions were validly reported. The studies examined spontaneous abortion in recognized pregnancies in cohorts of dry-cleaning and laundry work- ers; both reported an increased risk of spontaneous abortion in women who worked in dry-cleaning while pregnant. Nevertheless, both studies were limited by potential selection bias and small sample sizes and did not adequately address early fetal loss. They provide limited but supportive evidence of an association between tetrachloroethylene exposure and spontaneous abortion. The other study that EPA found compelling was that by Olsen et al. (1990); this study, although methodologically sound, was limited by the small number of events in the exposed groups. There was also limited evidence of effects of tetrachloroethylene exposure on the developing fetus in a well-designed study from Camp Lejeune, North Carolina (Sonnenfeld et al. 2001). An increase in small-for-gestational-age cases was observed in children born to older women and women who had a history of fetal loss, but little effect was observed in other segments of the population. That discrepancy was difficult to resolve and may be spurious. (After publication of this study, it was discovered that some members of the control population were misclassified and were actually exposed, so the analyses in the paper are no longer valid.) EPA is inconsistent in characterizing the strongest evidence of reproductive toxicity. In “Characterization of Hazard and Dose Response” (EPA 2008; Section 6.1.3, page 6-5, lines 5-6), EPA cites “some evidence for growth retardation in infants born to mothers residing in housing with drinking water contaminated with tetrachloroethylene” as the main evidence of a reproductive outcome of concern. That conflicts with the conclusions in Chapter 4, where EPA indicates that the strongest evidence is on spontaneous abortion on the ba- sis of the occupational studies. EPA also considered potential male-mediated effects of tetrachloroethyl- ene (Eskenazi et al. 1991a,b). Semen-analysis measures in dry-cleaning and

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48 Review of the EPA’s Draft IRIS Assessment of Tetrachloroethylene laundry workers were compared. The reported differences were subtle and did not always favor the exposed or unexposed. The second study examined total fertility in the wives of dry-cleaners by using standardized fertility ratios; this study was uninformative in that it was too small to evaluate fertility patterns. In general, the committee did not consider the draft section on adverse re- productive and developmental outcomes to be balanced in the presentation or critique of studies. The committee’s general impression was that the section focused primarily on studies that reported results that confirmed a positive asso- ciation and that the effect of methodologic limitations of the studies on the va- lidity of results was not fully appreciated. For example, in discussing possible reasons for failure to find associations between tetrachloroethylene exposure and adverse outcomes (page 4-121, line 33, through page 4-122, line 7), the draft did not consider the possibility that there is no association. In another case, the draft assessment refers to a “strong but imprecise association between IUGR [intrau- terine growth restriction] and exposure to tetrachloroethylene (OR =12.5, 95% CI not given” (page 4-122, lines 8-12), but this result is based on a single ex- posed case. EPA’s description suggests an impressive finding. A more appropri- ate discussion would have stated there were too few exposed cases to calculate a measure of association reliably and would not have cited the odds ratio. In addition, the draft includes some errors in reporting results. For exam- ple, the results of Windham et al. (1991; see page 4-120, lines 21-22) are re- ported to be adjusted for age, race, education, prior fetal loss, smoking, and number of hours worked, implying multivariable adjustment, whereas data were adjusted for these variables one at a time (see Windham et al. [1991], page 247, paragraph 3). Finally, the discrepancy in emphasizing spontaneous abortion as the out- come with the strongest evidence of an association with tetrachloroethylene ex- posure in Chapter 4 and intrauterine growth retardation in Chapter 6 suggests that the evidence on reproductive outcomes was not carefully evaluated. FINDINGS AND RECOMMENDATIONS EPA’s identification of the key animal and epidemiologic reproductive and developmental studies of tetrachloroethylene appears to be complete, but the committee recommends some reorganization and reconsideration of data to pro- vide a more transparent and balanced characterization of the data. The commit- tee agrees with the selection of the Tinston (1994) two-generation reproductive- toxicity study and the Carney et al. (2006) developmental-toxicity study as sup- portive of a point of departure and an RfV. EPA’s derivation of a comparative RfV based on the developmental toxicity of tetrachloroethylene is an important contribution to the tetrachloroethylene database. However, the committee rec- ommends that EPA revise the chapter to address the specific deficiencies dis- cussed above regarding information presented on the animal reproductive and developmental studies. In particular, the revision should include: (1) a critical

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49 Reproductive and Developmental Effects analysis of the described studies, including an assessment of the relationship of maternal toxicity to developmental toxicity and the strengths, limitations, and consistency of the various study results; (2) characterization of maternal toxicity (e.g., mild or severe) associated with the studies listed in Table 4-10 and use of consistent nomenclature (ppm or mg/m3) for listing tetrachloroethylene concen- trations; (3) the scientific basis for selecting the Tinston (1994) and Carney et al. (2006) studies as supportive of an RfV; (4) the scientific rationale for selecting the Tinston (1994) study instead of the Carney et al. (2006) study for derivation of the comparative RfV; (5) information on the mode of action for tetrachloro- ethylene-induced developmental toxicity which addresses the apparent contra- dictions raised in the committee’s review that TCA may be the causative agent; and (6) characterization of the evidence for tetrachloroethylene-induced repro- ductive and developmental toxicity in animals based on EPA risk assessment guidelines. Stating explicitly whether the animal evidence is sufficient or insuf- ficient for these important end points will help risk managers and others to more readily identify and protect against potential adverse health effects. It will also help to identify data gaps in the tetrachloroethylene database. In addition to re- vising the chapter, the committee also recommends that EPA consider conduct- ing a bench-mark dose analysis and deriving an RfV based on the Carney et al. (2006) study in addition to, or instead of, the Tinston (1994) study. This will address the potential confounding effects of maternal toxicity at the 1,000 ppm exposure level observed in the Tinston (1994) study.