Functional developmental toxicity

IUGR) with elevated risk levels of these diseases (Lau Rogers, 2005). The basis of the association is believed to be that alterations in nutrient availability (or other environmental stressors) lead to short-term adaptive measures in the fetus (involving altered homeostatic set-points) that later result in metabolic disorders when the stressor is relieved. The metabolic alterations, in turn, then gradually contribute to increased risk with ageing. It is important to note that functional developmental toxicity may be evident only after long latency periods and may be difficult to ascertain due to the functional reserve capacity of many organ systems. 

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Functional developmental toxicity is the study of alterations or delays in the physiological or biochemical competence of an organism or organ system after exposure to an agent during pre- or postnatal development. In any given test animal, delayed development can be assessed in relation to established landmarks for physical, behavioral, and sexual maturation. 

B. Conception to implantation Reproductive functions in the adult female, preimplantation and implantation stages of the conceptus. Segment I Segment I Segment I Multigeneration One-generation developmental toxicity... 

C. Implantation to closure of the hard palate Adult female reproductive functions and development of Segment I Segment II Segment I Segment II Segment II Multigeneration One-generation developmental toxicity Developmental neurotoxicity... 

Lochry, E.A. (1987). Concurrent use of behavioral/functional testing in existing reproductive and developmental toxicity screens Practical consideration. J. Am. Coll. Toxicol. 6 433-439. 

A full set of studies normally includes short-term and long-term animal studies on chronic effects and potential carcinogenicity, studies on reproductive and developmental toxicity, genotoxicity, kinetics and metabolism, pharmacological properties and special studies depending on the characteristics of the substance and observation in the standard set of studies. Human clinical studies may be necessary for substances which are metabolised and may interfere with functions of the human body. 

Toxicologists nowadays take a broad view of developmental toxicity they consider not only structural but also functional abnormalities to qualify as adverse, as long as they were produced as a result of exposures incurred in utero. Thus, for example, the developmental effects of chronic alcohol abuse by pregnant women, known as fetal alcohol syndrome (FAS), are characterized not only by the presence of certain craniofacial abnormalities, but also by a variety of disabilities such as shortened attention span, speech disorders, and restlessness. Although fully expressed physical deformities included in FAS are associated with heavy drinking, debate continues on the level of alcohol consumption, if any, that is without these more subtle effects on behavior. 

Developmental toxicity, defined in its widest sense to include any adverse effect on normal development either before or after birth, has become of increasing concern in recent years. Developmental toxicity can result from exposure of either parent prior to conception, from exposure of the embryo or fetus in utero or from exposure of the progeny after birth. Adverse developmental effects may be detected at any point in the life span of the organism. In addition to stmcmral abnormalities, examples of manifestations of developmental toxicity include fetal loss, altered growth, functional defects, latent onset of adult disease, early reproductive senescence, and shortened life span (WHO/IPCS 2001b). 

The term reproductive toxicity is sometimes used exclusively to describe toxic effects on male and female sexual function and fertility. More commonly, and in this book, reproductive effects are considered to include adverse effects on sexual function and fertility in males and females as well as developmental toxicity. 

The Guidelines for Developmental Toxicity Risk Assessment (US-EPA 1991) outline principles and methods for evaluating data from animal and human studies, exposure data, and other information to characterize risk to human development, growth, survival, and function because of exposure prior to conception, prenatally, or to infants and children. 

The focus of this chapter is on reproductive testing guidelines in the region. These test guidelines cover the assessment of fertility and other aspects of reproductive function in adults, prenatal developmental toxicity (including teratogenicity), and postnatal growth and development. 

Where functional cross-reactivity to at least one of the usual toxicology species is present, and appropriate assays for PK and PD have been developed, the clinical candidate can be used in a relatively conventional developmental toxicity program with that species (preferably the rat, for which the most background data will be available). Following early sub-chronic repeat-dose toxicity testing in the rodent (usually up to 1 month s duration), with accompanying PK/PD data, the reproductive study program can be planned as appropriate to the circumstances. 

The second objective of the hazard assessment concerns characterization of the identified hazards of a particular substance. Under REACH this means that the registrant must define so-called derived no-effect levels., abbreviated DNELs. With respect to human health, these values constitute exposure levels above which humans should not be exposed and below which risks for humans are considered controlled. The DNEL derivation is a complex process which comprises several conversion steps and the application of different assessment factors. In the case of reproductive toxicity, the registrant derives separate DNELs with respect to developmental toxicity on the one hand and to impairment of sexual function and fertility on the other hand. 

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