Developmental toxicity, definition

Developmental Toxicity. Three human studies that described congenital malformations as an end point allow no definitive conclusion to be drawn regarding an association between prenatal lead exposure and the occurrence of congenital anomalies (Emhart et al. 1985, 1986 McMichael et al. 1986 ... 

No definitive, quantitative data were available regarding the potential reproductive and developmental toxicity of arsine in humans. 

In vitro developmental toxicity systems have clearly been usefid for studies of mechanisms of developmental effects (e.g., Datson et al., 1989) — use (3) in the list above. It is unclear, though, whether in vitro developmental toxicity tests will provide useful information about developmental toxicity that is not derived from whole animal studies [use (4) from the list]. As is true for a possible use as a prescreen, the interpretation of a positive finding in an in vitro test will depend on knowing the exposure level in vivo. When this is known, the in vitro information could be helpful. The results of in vivo studies, though, would still likely be considered definitive for that species. 

The reproductive/developmental toxicity screening test can provide initial information on possible effects on reproduction and/or development and may make it possible to identify a substance as being toxic to reproduction, i.e., the test gives a clear positive result. However, this test offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. In addition, because of the study design (e.g., relatively small numbers of animals per dose level, relatively short smdy duration), the test will not provide evidence for definite claims of no effects. 

As to the interpretation of individual assay results, a reduction-istic assay will by definition not predict 100% of developmental toxicants tested, as for at least some of them the mechanism of developmental toxicity will not be covered within the assay. 

It is in this context, that in 2009, the DART committee formed a Steering Team to work on a project titled Consensus List of Developmental Toxicants. The Steering Team published a report of their deliberations and defined developmental toxicant in terms of its concentration in vitro (27). Daston et al. (27) based the definitions of positive and negative developmental toxicants according to their exposure conditions. That is, compounds on the list could have an exposure concentration that is unequivocally positive and a concentration that is unequivocally negative. In addition, only permanent effects that alter fetal organization, particularly structural malformations, were considered developmental toxicity. For example, fetal weight decreases (which are commonly used endpoints in risk assessment) are not considered developmental toxicity for the purposes of this list. 

Establish an international harmonized system for terminology and definitions for reproductive and developmental toxicity. 

Data for assessing reproductive or developmental toxicity are derived both from observations of humans and from experimental animal studies. It is beyond the scope of this document to enumerate the kinds of data that can permit a complete assessment of reproductive and developmental toxicity that covers all situations. The definition of a sufficient data set changes as scientific knowledge accumulates on specific agents and as the understanding of the predictive capabilities of animal models and other procedures improves. Appendix C and Appendix D of this document describe studies that commonly provide such information and offer guidance in their interpretation. 

For the purposes of this chapter, reproductive toxicity will refer to any manifestations of xenobiotic exposure, including endocrine disruption (see discussion below), reflecting adverse effects on any of the physiological processes and associated behaviors and/or anatomical structures involved in animal reproduction or development (Figure 36.1). This is a fairly broad definition which encompasses developmental toxicity, as well as any toxic... 

Definitive information regarding the acute toxicity of di-N-octylphthalate is not available. An estimated lethal oral dose in humans is between 0.5 and 15gkg, or between 1 oz equivalent to 29.6 mis and 1 qt equivalent to 0.96 liters in a 70 kg adult. Compounds that are structurally similar to di-N-oct-ylphthalate are known to irritate mucous membranes resulting in irritation of the eyes, throat, and upper respiratory tract passages and in gastrointestinal disturbances. There is evidence that some phthalates, such as di-s-octylphthalate, may be reproductive and developmental toxicants. Generally, the acute oral toxicity of alkylphthalates is low and the acute oral toxicity decreases as molecular weight increases. 

The proposed US EPA weight-of-evidence (WOE) scheme for suspect developmental toxicants defines three levels of confidence for data used to identify developmental hazards and to assess the risk of human developmental toxicity (1) definitive evidence for human developmental toxicity or for no apparent human developmental toxicity, (2) adequate evidence for potential human developmental toxicity or no apparent potential human developmental toxicity, and (3) inadequate evidence for determining potential human developmental toxicity. The scheme may require scientific judgment based on experience to weigh the implications of study design, statistical analyses, and biological significance of the data. 

Inhalation studies with mice and rats indicate that TCE is a developmental toxicant. Fetotoxicity is expressed mainly as skeletal ossification anomalies and other effects consistent with delayed maturation. Oral studies with rats and mice showed no trichloroethylene-related effects on fertility or other indicators of reproductive performance. No definitive teratogenic effects have been reported regarding exposure to TCE. 

Chang and Verity 1995 ATSDR 1999). Mitochondrial changes, induction of lipid peroxi tion, microtuble disruption, and disrupted protein synthesis have all been proposed as possible mechanisms. In developmental toxicity, disruption of cell-surface recognition has also been proposed as a possible mech sm (Baron et al. 1998 Dey et al. 1999). To date, no definitive data are available that point to any one mechanism as the proximate cause for the neurotoxic symptoms associated with MeHg exposure in adults. 

The EPA (2) has recently produced a good draft document for assessment of developmental toxicants and to be consistent the same or equivalent definitions and terminology are used. 

There exists evidence that some insects store dietary alkaloids derived from natural sources. Figure 98 presents insect species that are known to accumulate pyrrolizidine alkaloids during different developmental stages. The larvae and adults of these insects can metabolize pyrrolizidine alkaloids in current physiological activities. These alkaloids are not toxic for these organisms. Moreover, there is observed trace accumulation of a portion of these compounds in the liver. There is no definitive purpose for these traces. Generally, the opinion presented in 1888 by Stahl in Germany that the accumulation of alkaloids is for defensive purposes has been most often cited in the research literature. 

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