User Guide to Thresholds and Classification - Environmental ...

240User Guide for Thresholds and Classificationsembryo or foetus first, and then evaluate maternal toxicity, along with any other factors, that are likely tohave influenced these effects, as part of the weight of evidence. In general, developmental effects that areobserved at maternally toxic doses should not be automatically discounted. Discounting developmentaleffects that are observed at maternally toxic doses can be done only on a case-by-case basis when a causalrelationship is established or refuted.If appropriate information is available, it is important to try to determine whether developmental toxicity is dueto a specific maternally mediated mechanism or to a non-specific secondary mechanism, like maternal stressand the disruption of homeostasis. Generally, the presence of maternal toxicity should not be used to negatefindings of embryo or foetal effects, unless it can be clearly demonstrated that the effects are secondary nonspecificeffects. This is especially the case when the effects in the offspring are significant, for example,irreversible effects such as structural malformations. In some situations, it is reasonable to assume thatreproductive or developmental toxicity is due to a secondary consequence of maternal toxicity and discountthe effects; for example, if the chemical is so toxic that dams fail to thrive and there is severe inanition, theyare incapable of nursing pups, or they are prostrate or dying.16.2.4. Maternal toxicityDevelopment of the offspring throughout gestation and during the early postnatal stages can be influencedby toxic effects in the mother through non-specific mechanisms related to stress and the disruption ofmaternal homeostasis, or by specific maternally mediated mechanisms. This can occur in the context of adevelopmental or a reproductive toxicity study (one- or two-generation study). Therefore, in the interpretationof the developmental outcome to decide classification for developmental effects it is important to considerthe possible influence of maternal toxicity. This is a complex issue because of uncertainties surrounding therelationship between maternal toxicity and developmental outcome. Expert judgement and a weight-ofevidenceapproach, using all available studies, should be used to determine the degree of influence thatshould be attributed to maternal toxicity when interpreting the criteria for classification for developmentaleffects. The adverse effects in the embryo or foetus should be first considered, and then maternal toxicity,along with any other factors that are likely to have influenced these effects, using a weight-of-evidenceapproach to reach a conclusion about classification.Based on pragmatic observation, it is believed that maternal toxicity may, depending on severity, influencedevelopment via non-specific secondary mechanisms, producing effects such as depressed foetal weight,retarded ossification, and possibly resorptions and certain malformations in some strains of certain species.However, the limited numbers of studies that have investigated the relationship between developmentaleffects and general maternal toxicity have failed to demonstrate a consistent, reproducible relationshipacross species. Developmental effects, which occur even in the presence of maternal toxicity, areconsidered evidence of developmental toxicity, unless it can be unequivocally demonstrated on a case-bycasebasis that the developmental effects are secondary to maternal toxicity. Moreover, classification shouldbe considered when there is significant toxic effect in the offspring, for example, irreversible effects such asstructural malformations, embryo or foetal lethality, and significant post-natal functional deficiencies.January 2012 EPA0109