Immune system, reproductive/developmental

The priority effects are carcinogenicity, mutagenicity, reproductive or developmental toxicity, endocrine disruption and neurotoxicity. Human toxicity is broader than priority effects, including acute toxicity, systemic toxicity (organ effects), immune system effects and skin/eye/respiratory damageaswellasthepriority effects. And toxicity as T includes both human toxicity and ecotoxicity. 

The three targets that are the first point of contact between environmental chemicals and the body will be discussed first the gastrointestinal tract, the respiratory system, and the skin. Recall from Chapter 2 that chemicals enter the blood after absorption, so this fluid is the next target (see Figure 2.1). Then come the liver, the kidneys, and the nervous system. The chapter concludes with a discussion of some chemicals that can damage the reproductive system and some that can cause birth defects, the so-called teratogens, and other forms of developmental toxicity. Brief discussions of immune system, cardiovascular system, muscle, and endocrine system toxicities are also offered. 

Taurine deficiency is rare in adult humans but is common in domestic cats, due to poor absorption from tinned catfood. Consequences of taurine deficiency in cats are cardiomyopathy, retinal degradation, reproductive failure in females, developmental abnormalities and impairment of the immune system. It is possible that a chronic deficiency in humans may have similar effects. 

Reproductive toxicity to 2,3,7,8-TCDD has been demonstrated in animals. "" The effects include pre- and postimplantation losses in females, morphologic and functional changes in male and female reproductive organs, and hormonal imbalance in both sexes. A number of developmental effects have been observed in animals acutely exposed to 2,3,7,8-TCDD by the oral route. Effects observed in offspring of animals include cleft palate, kidney anomalies, immune system damage (thymic atrophy and immunosuppression), impaired development of the reproductive system, decreased growth, and fetal/newborn mortality. 

As shown in Figure 2-4, there is a considerable body of data on the health effects of carbon tetrachloride in humans, especially following acute oral or inhalation exposures. Although many of the available reports lack quantitative information on exposure levels, the data are sufficient to derive approximate values for safe exposure levels. There is limited information on the effects of intermediate or chronic inhalation exposure in the workplace, but there are essentially no data on longer-term oral exposure of humans to carbon tetrachloride, most toxicity studies have focuses on the main systemic effects of obvious clinical significance (hepatotoxicity, renal toxicity, central nervous system depression). There are data on the effects of carbon tetrachloride on the immune system, but there are no reports that establish whether or not developmental, reproductive, genotoxic, or carcinogenic effects occur in humans exposed to carbon tetrachloride. 

During the out-of-season periods, reproductive hormone secretion and gonadal activity are at a complete halt. Although the basic reproductive and developmental physiology appear similar to human in the rhesus monkey and many endpoint parameters are established, the distinct reproductive seasonality requires special timing and has practical implications for widespread use of this model for DART studies. With regard to immune system evaluation it can be assumed that most of the available tests for cynomolgus monkey will also be applicable to rhesus monkeys. 

The endpoints measured in the developmental and reproductive toxicity (DART) study are consistent with studies conducted on small molecules and biotherapeutics. For further information, see FDA and International Conference on Harmonization (ICH) guidelines. Organs essential to the normal functioning of the immune system are not typically assessed in DART studies, and revisiting this should be considered as suggested by Holsapple et al.37... 

Animal Slight liver and kidney damage occurred after chronic (1 or 2 years) exposure to high dose of bromoform. No developmental and reproductive effects were observed. Dose-dependent fatty changes and minimal liver necrosis were observed at 100 or 200 mg kg by corn oil gavage, for 103 weeks, to rats and female mice. Rats exposed for 2 years appeared to have decreased resistance to viral infection due to functional impairment of immune system. Two-year exposure to 200 mg kg resulted in dose-related incidences of squamous metaplasia of the prostate gland in male rats. 

Developmental effects discussed in this section are restricted mainly to effects on fetal development, birth weight and weight gain in early life, and teratogenicity. Information regarding effects on the thyroid, immune system, and reproduction in offspring following perinatal exposure to PCBs is presented in Sections 3.2.3, 3.2.4, and 3.2.5, respectively. 

The health-effects data on JP-8 and related fuels were reviewed for the following end points respiratory tract toxicity, neurotoxicity, immunotoxicity, liver toxicity, kidney toxicity, reproductive and developmental toxicity, cardiovascular toxicity, genotoxicity, and carcinogenicity. JP-8 was found to be potentially toxic to the immune system, respiratory tract, and nervous system at exposure concentrations near the interim PEL of350 mg/m3. Those toxicides are summarized below. 

One advantage of rodents, beyond the exceptionally well-characterized immune system and availability of reagents, is the fact that DIT assessment may be able to be dovetailed into existing developmental and reproductive assessments. Certainly DIT testing using other mammalian species may be appropriate under some circumstances, but the opportunity to examine developmental immunotoxicity, developmental neurotoxicity, and reproductive toxicity using a common model suggests that the rodent is likely to remain the standard model of choice. This conclusion was also reached by various consensus panels (Holsapple et al., 2005). 

Receptor-xenobiotic interactions have been associated with immune, CNS, endocrine, cardiovascular system (CVS), developmental, and reproductive system effects as well as with carcinogenesis. A sampling of toxic chemicals that bind with receptors and their effects are listed in Table 4.3. 

Developmental retardation Male reproductive system Female reproductive system Endocrine system Immune system Respiratory system Gastrointestinal system... 

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