- Email: [email protected]
A perspective on the significance of maternally mediated developmental toxicity
REGULATORY
TOXICOLOGY
AND
PHARMACOU)CY
l&144-
148 (1989)
A Perspective on the Significance of Maternally Mediated Developmental Toxicity RONALD D. HOOD Department of Biology, The University ofAlabama, Tuscaloosa, Alabama 35487-0344, and R. D. Hood&Associates, Consulting Toxicologists, Northport, Alabama 35476
Received January 26, 1989
The significance of maternally mediated developmental toxicity has been controversial from both a biological and a regulatory point of view. The open literature has at times been interpreted to mean that a number of the effects seen in fetuses from dams exposed to maternally toxic doses of chemicals were secondary consequences of maternal toxicity rather than direct effects on the conceptus. Recent experimental studies, however, indicate that although certain relatively species-specific manifestations of developmental toxicity may at times be maternally mediated, most are not. On occasion, even severe maternal toxicity can apparently occur without causing readily discernible effects on the embryo/fetus. The most important concern of a regulatory agency with regard to developmental toxicity is the possibility of the causation of significant, irreversible harm to the offspring. In practical terms, the margin of safety for exposure to a developmental toxicant is of much more importance than whether or not the agent’s effects are maternally mediated. For protection of the unborn, it is,obviously the end result that matters, regardless of the mechanism. Safeguarding the conceptus from specific developmental toxicants (i.e., agents with relatively high A/D ratios) requires the use of safety factors based on the developmental toxicity NOEL. Protecting the conceptus against agents with A/D ratios near unity could be based on the maternal toxicity NOEL, however, as the true NOEL for developmental toxicity may be near that for the mother, but the adult NOEL is likely to be more readily determinable. 0 1989 Academic press, IIIC.
In recent years, considerable interest has been engendered in the relationship between adverse effects on the mother caused by exposure to chemicals during pregnancy and possible indirect effects on the conceptus. A series of papers by Khera ( 1984, 1985, 1987a,b) has provided much of the impetus for the renewed interest in “maternal effects.” It is now well established that deleterious influences resulting from maternal toxicity can indeed affect the conceptus. In fact, it appears likely that disruption of embryo/fetal development may result from direct effects on the conceptus, from maternally mediated effects, or from a combination of the two (DeSesso, 1987). Although maternal toxicity can lead to effects on the offspring, controversy remains regarding the regulatory and biological significance and prevalence of such effects I44 0273-2300189 $3.00 Copyright Q 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.
MATERNALLY
MEDIATED
DEVELOPMENTAL
TOXICITY
145
(Neubert and Barrach, 1983), as well as how they might be distinguished from direct effects on the conceptus. Although the basic premise that maternally mediated effects exist has been accepted, Khera’s concepts of the relationship between maternal and developmental toxicity (Khera, 1984, 1985, 1987a,b) have been criticized. For example, Palmer (1987) has suggested that because of the relative lack of negative data in the open literature, retrospective analyses such as Khera’s are unavoidably subject to selection bias. Further, there may be bases other than maternal mediation for the prevalence of certain categories of developmental defects in litters from rodents and rabbits subjected to maternally toxic doses of chemical agents. Because of factors such as regulative and repair abilities, intrinsic lack of specific sensitivity (e.g., due to lack of target receptors in the embryo/fetus that are present in maternal tissues), lack of activating enzyme activities, or decreased dose delivered to the offspring, the mammalian conceptus may be no more vulnerable or even less vulnerable to the effects of many chemical agents than is the dam (Johnson, 1987; Hood, 1989). Also, although certain developmental toxicants appear to act directly on the embryo/fetus by way of interacting with specific receptors (Pratt, 1985), many are probably relatively nonspecific cytotoxic agents that are considerably less selectively toxic to the conceptus. This is particularly true when agents are administered throughout organogenesis, as is often the case in studies done for the purpose of safety evaluation. Since a given strain or species is likely to have especially vulnerable points in its developmental program and any developing offspring may have only a limited repertoire of responses to adverse influences, a variety of toxic insults may lead to only a few relatively common endpoints, even when the toxicant is acting directly on the conceptus. Because the issue of maternally mediated developmental toxicity is an important one, it raises concerns that are subject to misunderstanding and misinterpretation. For example, it does not appear reasonable to assume that most manifestations of developmental toxicity seen in offspring of intoxicated dams are the result of maternally mediated effects. Primarily because of data from prospective studies (e.g., Kavlock et al., 1985; Beyer and Chernoff, 1986; Chemoff et al., 1987), it has become increasingly apparent that maternal toxicity is not invariably followed by the types of untoward effects on the offspring cataloged by Khera ( 1984, 1985) although more subtle effects could be present but are usually unlooked-for (e.g., Barlow et al., 1978, 1979). When possibly maternally mediated effects of chemical agents are seen, they may be confined to one or only a few somewhat species-specific endpoints. Even in such cases, a cause and effect relationship remains unproven. Critical analysis by others (e.g., Francis and Farland, 1987; Hardin, 1987; Palmer, 1987; Seidenberg and Becker, 1987) supports the contention that maternal toxicity is not invariably followed by discernible effects on the offspring, such as altered morphology, decreased size, or increased mortality. There are several important concerns with regard to risk assessment in developmental toxicity. One is the issue of whether animal models predict human outcomes, particularly in terms of our ability to predict biologically significant, irreversible effects- In this case maternal effects are a possible confounding factor in that they might differ between man and the test species. Another issue is that of margins of safety, and the likehhood that human exposure will exceed the developmental toxicity threshold for a given agent. When chemically induced developmental toxicity is
146
RONALD
D. HOOD
most often seen only at exposure levels that are at or near maternally toxic doses, maternal toxicity should be useful as a surrogate for developmental toxicity in determining NOELs for use in risk assessment. This is because adult toxicity is often discernible at exposure levels below those that result in clearly defined manifestations of hazard to the conceptus. Heightened concern regarding the relationship of maternal and developmental toxicity has resulted in the emergence of certain concepts. One states that toxicants which exert their effects on the conceptus at exposure levels considerably less than those required to induce maternal toxicity are of particular concern as unique “developmental toxicants” or “developmental hazards” (e.g., Johnson, 1984). Another concept that has been suggested is that agents appearing to cause developmental toxicity only at exposure levels that are also harmful to the mother (i.e., agents with low A/D ratios) are of relatively lesser concern. This assumes that discernibly toxic maternal exposures would commonly be avoided. That this proposed rule is potentially dangerous is indicated by exceptions that are of obvious importance because damage to the offspring may be permanent and debilitating. These include maternal ethanol consumption, cigarette smoking, and use of certain drugs with low therapeutic indices (e.g., isotretinoin). Thus, a more critical consideration must be the relative degree of harm to the conceptus in comparison with the effect on the mother. The most dangerous agents would then be those that are capable of “. . . inducing a magnitude or quality of effect beyond that which might be expected from the maternal effects observed,” as stated by Palmer (1987). This would be the case regardless of the presence or absence of maternal mediation of the effect on the offspring. The increased hazard from agents with high A/D ratios (Johnson, 1984) arises from the fact that a pregnant woman might be less likely to detect and (presumably) avoid such agents as opposed to those that cause unpleasant symptoms for her. Even in the case of agents with low A/D ratios, avoidance does not always occur, however, as can be seen from consideration of the examples given above. Such considerations persuaded participants at the recent EPA-sponsored Consensus Workshop on the Evaluation of Maternal and Developmental Toxicity to conclude that a developmental toxicity hazard assessment was necessary whenever deleterious effects on the embryo/fetus were observed, regardless of the apparent presence or absence of maternal toxicity (Kimmel et al., 1987). In view of the assumptions stated above, a further proposal comes to mind. “Maternal toxicity” may prove to be an important source of human developmental toxicity (e.g., Khera, 1987a,b), or adverse developmental effects seen at maternally toxic dose levels may merely occur as a consequence of the equal vulnerability of mother and conceptus. Regardless of which view is correct (and either or both may be in effect in a given situation), the implication remains that we must be especially careful to avoid exposure of pregnant mothers to chemicals at levels that may cause even apparently minor adverse effects on the mother, lest we cause miscarriage or congenital defects in addition to the adult toxicity. If one accepts the concept of maternally mediated adverse developmental effects in man and/or the reality of coaffective human teratogens, the obvious conclusion is that we must assiduously attempt to avoid maternal toxic insult, as the result might be not only an intoxicated mother but also a potentially defective child. In reality, it is of little consequence to the embryo/fetus whether it was harmed by a chemical that acted directly or through maternal mediation.
MATERNALLY
MEDIATED
DEVELOPMENTAL
TOXICITY
147
At the time of a toxic insult, the mother and conceptus are inseparable. Thus, unless there is reason to believe (in a particular case) that the cause of positive results in a developmental toxicity test is maternally mediated and that the maternal effect(s) involved is unique to the test species, maternal toxicity is not of paramount importance for the purpose of determining whether or not a human offspring might be affected. Once one ascertains whether there are effects on the ofTspring, then it is important to determine as much as possible about the mechanism(s) involved, but if the same mechanism(s) may occur in man, it does not matter whether the effect on the embryo/fetus is direct or indirect. All that truly matters in such a case is the final outcome.
ACKNOWLEDGMENTS The helpful comments of E. M. Johnson and F. Welsch regarding preliminary drafts of this manuscript are gratefully acknowledged.
REFERENCES BARLOW, S. M., KNIGHT, A. F., AND SULLIVAN. F. M. (I 978). Delay in postnatal growth and development of offspring produced by maternal restraint stress during pregnancy in the rat. Teratology IS,2 I I-2 18. BARLOW. S. M., KNIGHT, A. F., AND SULLIVAN, F. M. (1979). Prevention by diazepam of adverse effects of maternal restraint stress on postnatal development in the rat. Teratology 19, 105-I 10. BEYER, P. E., AND CHERNOFF, N. (1986). The induction ofsupernumerary ribs in rodents: Role of maternal stress. Teratogen, Carcinogen, Mutagen. 6,4 19-429. CHERNOFF, N., KAVLOCK, R. J., BEYER, P. E., AND MILLER, D. (1987). The potential relationship of maternal toxicity, genera1 stress, and fetal outcome. Teratogen. Carcinogen. Mutagen. 7,241-253. DESESSO, J. M. (1987). Maternal factors in developmental toxicity. Teratogen. Carcinogen. Mutagen. 7, 225-240.
FRANCIS, E. Z., AND FARLAND, W. H. (1987). Application of the preliminary developmental toxicity screen for chemical hazard identification under the Toxic Substances Control Act. Teratogen. Carcinogen. Mutagen. 7, 107-l 17. HARDIN, B. D. (1987). A recommended protocol for the Chernoff-Kavlock preliminary developmental toxicity test and a proposed method for assigning priority scores based on results of that test. Teratogen. Carcinogen. Mutagen. 7,85-94. HOOD, R. D. (1989). Maternal vs. developmental toxicity. In Research Needs .for Risk Assessment in Developmental Toxicology (R. D. Hood, Ed.), in press. NTIS, Washington, DC. JOHNSON, E. M. (1984). A prioritization and biological decision tree for developmental toxicity safety evaluations. J. Amer. Coil. Toxicol. 3, 14 1- 147. JOHNSON, E. M. (1987). A tier system for developmental toxicity evaluations based on considerations of exposure and effect relationships. Teratology 35,405-427. KAVLOCK, R. J., CHERNOFF, N., AND ROGERS, E. H. (1985). The effect of acute maternal toxicity on fetal development in the mouse. Teratogen. Carcinogen. Mutagen. 5,3- 13. KHERA, K. S. (I 984). Maternal toxicity-A possible factor in fetal malformations in mice. Teratology 29, 41 l-416. KHERA, K. S. (1985). Maternal toxicity: A possible etiological factor in embryo-fetal deaths and fetal malformations of rodent-rabbit species. Teratology31, 129-I 53. KHERA, K. S. (1987a). Maternal toxicity of drugs and metabolic disorders-A possible etiologic factor in the intrauterine death and congenital malformation: A critique on human data. CRC Crit. Rev. Toxicol. 17.345-375.
KHERA, K. S. (1987b). Maternal toxicity in humans and animals: Effects on fetal development and criteria for detection. Teratogen. Carcinogen. Mutagen. 7,287-295.
148
RONALD
D. HOOD
KIMMEL, G. L., KIMMEL, C. A., AND FRANCIS, E. Z. (1987). Implications of the consensus workshop on the evaluation of maternal and developmental toxicity. Terutogen. Carcinogen. Mutagen. 7,329-338. NEUBERT, D., AND BARRACH, H.-J. (1983). Effect of environmental agents on embryonic development and the applicability of in vitro techniques for teratological testing. In In Vitro Toxicity Testing of Environmental Agents (A. Kolher, T. K. Wong, L. D. Grant, R. S. DeWoskin, and T. J. Hughes, Eds.), pp. 147-172. Plenum, New York. PALMER, A. K. (1987). An indirect assessment of the Chernoff/Kavlock assay. Teratogen. Carcinogen. Mutagen. 7,95-106. PRATT, R. M. (1985). Receptor dependent mechanisms ofglucocorticoid and dioxin-induced cleft palate. Environ. Health Perspect. 61,35-40. SEIDENBERG, J. M., AND BECKER, R. A. (1987). A summary of the results of 55 chemicals screened for developmental toxicity in mice. Teratogen. Carcinogen. Mutagen. 7, 17-28.
TOXICOLOGY
AND
PHARMACOU)CY
l&144-
148 (1989)
A Perspective on the Significance of Maternally Mediated Developmental Toxicity RONALD D. HOOD Department of Biology, The University ofAlabama, Tuscaloosa, Alabama 35487-0344, and R. D. Hood&Associates, Consulting Toxicologists, Northport, Alabama 35476
Received January 26, 1989
The significance of maternally mediated developmental toxicity has been controversial from both a biological and a regulatory point of view. The open literature has at times been interpreted to mean that a number of the effects seen in fetuses from dams exposed to maternally toxic doses of chemicals were secondary consequences of maternal toxicity rather than direct effects on the conceptus. Recent experimental studies, however, indicate that although certain relatively species-specific manifestations of developmental toxicity may at times be maternally mediated, most are not. On occasion, even severe maternal toxicity can apparently occur without causing readily discernible effects on the embryo/fetus. The most important concern of a regulatory agency with regard to developmental toxicity is the possibility of the causation of significant, irreversible harm to the offspring. In practical terms, the margin of safety for exposure to a developmental toxicant is of much more importance than whether or not the agent’s effects are maternally mediated. For protection of the unborn, it is,obviously the end result that matters, regardless of the mechanism. Safeguarding the conceptus from specific developmental toxicants (i.e., agents with relatively high A/D ratios) requires the use of safety factors based on the developmental toxicity NOEL. Protecting the conceptus against agents with A/D ratios near unity could be based on the maternal toxicity NOEL, however, as the true NOEL for developmental toxicity may be near that for the mother, but the adult NOEL is likely to be more readily determinable. 0 1989 Academic press, IIIC.
In recent years, considerable interest has been engendered in the relationship between adverse effects on the mother caused by exposure to chemicals during pregnancy and possible indirect effects on the conceptus. A series of papers by Khera ( 1984, 1985, 1987a,b) has provided much of the impetus for the renewed interest in “maternal effects.” It is now well established that deleterious influences resulting from maternal toxicity can indeed affect the conceptus. In fact, it appears likely that disruption of embryo/fetal development may result from direct effects on the conceptus, from maternally mediated effects, or from a combination of the two (DeSesso, 1987). Although maternal toxicity can lead to effects on the offspring, controversy remains regarding the regulatory and biological significance and prevalence of such effects I44 0273-2300189 $3.00 Copyright Q 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.
MATERNALLY
MEDIATED
DEVELOPMENTAL
TOXICITY
145
(Neubert and Barrach, 1983), as well as how they might be distinguished from direct effects on the conceptus. Although the basic premise that maternally mediated effects exist has been accepted, Khera’s concepts of the relationship between maternal and developmental toxicity (Khera, 1984, 1985, 1987a,b) have been criticized. For example, Palmer (1987) has suggested that because of the relative lack of negative data in the open literature, retrospective analyses such as Khera’s are unavoidably subject to selection bias. Further, there may be bases other than maternal mediation for the prevalence of certain categories of developmental defects in litters from rodents and rabbits subjected to maternally toxic doses of chemical agents. Because of factors such as regulative and repair abilities, intrinsic lack of specific sensitivity (e.g., due to lack of target receptors in the embryo/fetus that are present in maternal tissues), lack of activating enzyme activities, or decreased dose delivered to the offspring, the mammalian conceptus may be no more vulnerable or even less vulnerable to the effects of many chemical agents than is the dam (Johnson, 1987; Hood, 1989). Also, although certain developmental toxicants appear to act directly on the embryo/fetus by way of interacting with specific receptors (Pratt, 1985), many are probably relatively nonspecific cytotoxic agents that are considerably less selectively toxic to the conceptus. This is particularly true when agents are administered throughout organogenesis, as is often the case in studies done for the purpose of safety evaluation. Since a given strain or species is likely to have especially vulnerable points in its developmental program and any developing offspring may have only a limited repertoire of responses to adverse influences, a variety of toxic insults may lead to only a few relatively common endpoints, even when the toxicant is acting directly on the conceptus. Because the issue of maternally mediated developmental toxicity is an important one, it raises concerns that are subject to misunderstanding and misinterpretation. For example, it does not appear reasonable to assume that most manifestations of developmental toxicity seen in offspring of intoxicated dams are the result of maternally mediated effects. Primarily because of data from prospective studies (e.g., Kavlock et al., 1985; Beyer and Chernoff, 1986; Chemoff et al., 1987), it has become increasingly apparent that maternal toxicity is not invariably followed by the types of untoward effects on the offspring cataloged by Khera ( 1984, 1985) although more subtle effects could be present but are usually unlooked-for (e.g., Barlow et al., 1978, 1979). When possibly maternally mediated effects of chemical agents are seen, they may be confined to one or only a few somewhat species-specific endpoints. Even in such cases, a cause and effect relationship remains unproven. Critical analysis by others (e.g., Francis and Farland, 1987; Hardin, 1987; Palmer, 1987; Seidenberg and Becker, 1987) supports the contention that maternal toxicity is not invariably followed by discernible effects on the offspring, such as altered morphology, decreased size, or increased mortality. There are several important concerns with regard to risk assessment in developmental toxicity. One is the issue of whether animal models predict human outcomes, particularly in terms of our ability to predict biologically significant, irreversible effects- In this case maternal effects are a possible confounding factor in that they might differ between man and the test species. Another issue is that of margins of safety, and the likehhood that human exposure will exceed the developmental toxicity threshold for a given agent. When chemically induced developmental toxicity is
146
RONALD
D. HOOD
most often seen only at exposure levels that are at or near maternally toxic doses, maternal toxicity should be useful as a surrogate for developmental toxicity in determining NOELs for use in risk assessment. This is because adult toxicity is often discernible at exposure levels below those that result in clearly defined manifestations of hazard to the conceptus. Heightened concern regarding the relationship of maternal and developmental toxicity has resulted in the emergence of certain concepts. One states that toxicants which exert their effects on the conceptus at exposure levels considerably less than those required to induce maternal toxicity are of particular concern as unique “developmental toxicants” or “developmental hazards” (e.g., Johnson, 1984). Another concept that has been suggested is that agents appearing to cause developmental toxicity only at exposure levels that are also harmful to the mother (i.e., agents with low A/D ratios) are of relatively lesser concern. This assumes that discernibly toxic maternal exposures would commonly be avoided. That this proposed rule is potentially dangerous is indicated by exceptions that are of obvious importance because damage to the offspring may be permanent and debilitating. These include maternal ethanol consumption, cigarette smoking, and use of certain drugs with low therapeutic indices (e.g., isotretinoin). Thus, a more critical consideration must be the relative degree of harm to the conceptus in comparison with the effect on the mother. The most dangerous agents would then be those that are capable of “. . . inducing a magnitude or quality of effect beyond that which might be expected from the maternal effects observed,” as stated by Palmer (1987). This would be the case regardless of the presence or absence of maternal mediation of the effect on the offspring. The increased hazard from agents with high A/D ratios (Johnson, 1984) arises from the fact that a pregnant woman might be less likely to detect and (presumably) avoid such agents as opposed to those that cause unpleasant symptoms for her. Even in the case of agents with low A/D ratios, avoidance does not always occur, however, as can be seen from consideration of the examples given above. Such considerations persuaded participants at the recent EPA-sponsored Consensus Workshop on the Evaluation of Maternal and Developmental Toxicity to conclude that a developmental toxicity hazard assessment was necessary whenever deleterious effects on the embryo/fetus were observed, regardless of the apparent presence or absence of maternal toxicity (Kimmel et al., 1987). In view of the assumptions stated above, a further proposal comes to mind. “Maternal toxicity” may prove to be an important source of human developmental toxicity (e.g., Khera, 1987a,b), or adverse developmental effects seen at maternally toxic dose levels may merely occur as a consequence of the equal vulnerability of mother and conceptus. Regardless of which view is correct (and either or both may be in effect in a given situation), the implication remains that we must be especially careful to avoid exposure of pregnant mothers to chemicals at levels that may cause even apparently minor adverse effects on the mother, lest we cause miscarriage or congenital defects in addition to the adult toxicity. If one accepts the concept of maternally mediated adverse developmental effects in man and/or the reality of coaffective human teratogens, the obvious conclusion is that we must assiduously attempt to avoid maternal toxic insult, as the result might be not only an intoxicated mother but also a potentially defective child. In reality, it is of little consequence to the embryo/fetus whether it was harmed by a chemical that acted directly or through maternal mediation.
MATERNALLY
MEDIATED
DEVELOPMENTAL
TOXICITY
147
At the time of a toxic insult, the mother and conceptus are inseparable. Thus, unless there is reason to believe (in a particular case) that the cause of positive results in a developmental toxicity test is maternally mediated and that the maternal effect(s) involved is unique to the test species, maternal toxicity is not of paramount importance for the purpose of determining whether or not a human offspring might be affected. Once one ascertains whether there are effects on the ofTspring, then it is important to determine as much as possible about the mechanism(s) involved, but if the same mechanism(s) may occur in man, it does not matter whether the effect on the embryo/fetus is direct or indirect. All that truly matters in such a case is the final outcome.
ACKNOWLEDGMENTS The helpful comments of E. M. Johnson and F. Welsch regarding preliminary drafts of this manuscript are gratefully acknowledged.
REFERENCES BARLOW, S. M., KNIGHT, A. F., AND SULLIVAN. F. M. (I 978). Delay in postnatal growth and development of offspring produced by maternal restraint stress during pregnancy in the rat. Teratology IS,2 I I-2 18. BARLOW. S. M., KNIGHT, A. F., AND SULLIVAN, F. M. (1979). Prevention by diazepam of adverse effects of maternal restraint stress on postnatal development in the rat. Teratology 19, 105-I 10. BEYER, P. E., AND CHERNOFF, N. (1986). The induction ofsupernumerary ribs in rodents: Role of maternal stress. Teratogen, Carcinogen, Mutagen. 6,4 19-429. CHERNOFF, N., KAVLOCK, R. J., BEYER, P. E., AND MILLER, D. (1987). The potential relationship of maternal toxicity, genera1 stress, and fetal outcome. Teratogen. Carcinogen. Mutagen. 7,241-253. DESESSO, J. M. (1987). Maternal factors in developmental toxicity. Teratogen. Carcinogen. Mutagen. 7, 225-240.
FRANCIS, E. Z., AND FARLAND, W. H. (1987). Application of the preliminary developmental toxicity screen for chemical hazard identification under the Toxic Substances Control Act. Teratogen. Carcinogen. Mutagen. 7, 107-l 17. HARDIN, B. D. (1987). A recommended protocol for the Chernoff-Kavlock preliminary developmental toxicity test and a proposed method for assigning priority scores based on results of that test. Teratogen. Carcinogen. Mutagen. 7,85-94. HOOD, R. D. (1989). Maternal vs. developmental toxicity. In Research Needs .for Risk Assessment in Developmental Toxicology (R. D. Hood, Ed.), in press. NTIS, Washington, DC. JOHNSON, E. M. (1984). A prioritization and biological decision tree for developmental toxicity safety evaluations. J. Amer. Coil. Toxicol. 3, 14 1- 147. JOHNSON, E. M. (1987). A tier system for developmental toxicity evaluations based on considerations of exposure and effect relationships. Teratology 35,405-427. KAVLOCK, R. J., CHERNOFF, N., AND ROGERS, E. H. (1985). The effect of acute maternal toxicity on fetal development in the mouse. Teratogen. Carcinogen. Mutagen. 5,3- 13. KHERA, K. S. (I 984). Maternal toxicity-A possible factor in fetal malformations in mice. Teratology 29, 41 l-416. KHERA, K. S. (1985). Maternal toxicity: A possible etiological factor in embryo-fetal deaths and fetal malformations of rodent-rabbit species. Teratology31, 129-I 53. KHERA, K. S. (1987a). Maternal toxicity of drugs and metabolic disorders-A possible etiologic factor in the intrauterine death and congenital malformation: A critique on human data. CRC Crit. Rev. Toxicol. 17.345-375.
KHERA, K. S. (1987b). Maternal toxicity in humans and animals: Effects on fetal development and criteria for detection. Teratogen. Carcinogen. Mutagen. 7,287-295.
148
RONALD
D. HOOD
KIMMEL, G. L., KIMMEL, C. A., AND FRANCIS, E. Z. (1987). Implications of the consensus workshop on the evaluation of maternal and developmental toxicity. Terutogen. Carcinogen. Mutagen. 7,329-338. NEUBERT, D., AND BARRACH, H.-J. (1983). Effect of environmental agents on embryonic development and the applicability of in vitro techniques for teratological testing. In In Vitro Toxicity Testing of Environmental Agents (A. Kolher, T. K. Wong, L. D. Grant, R. S. DeWoskin, and T. J. Hughes, Eds.), pp. 147-172. Plenum, New York. PALMER, A. K. (1987). An indirect assessment of the Chernoff/Kavlock assay. Teratogen. Carcinogen. Mutagen. 7,95-106. PRATT, R. M. (1985). Receptor dependent mechanisms ofglucocorticoid and dioxin-induced cleft palate. Environ. Health Perspect. 61,35-40. SEIDENBERG, J. M., AND BECKER, R. A. (1987). A summary of the results of 55 chemicals screened for developmental toxicity in mice. Teratogen. Carcinogen. Mutagen. 7, 17-28.