Short-term toxicity and reproduction studies in rats with hexachloro-(1,3)-butadiene

In rats given daily doses of 0. 0.4, 1.0, 2.5, 6.3, and 15.6 mg of hexachloro-(1,3)-buta-diene (HCBD)/kg by gavage for 13 weeks, no effect levels of 1.0 and 2.5 mg/kg were established for females and males, respectively. Inhibition of growth occurred in both sexes at the two highest doses and degeneration of proximal renal tubules occurred at doses of 2.5 and 6.3 mg/kg or more in females and males, respectively. Urine-concentrating ability was significantly reduced in females at doses of 2.5 mg/kg or more and in males at 15 mg/kg. Relative kidney weights were increased at the two highest doses in both sexes. Increased cytoplasmic basophilia of hepatocytes occurred in males at the two highest doses, associated with an increase in liver weight. In females, liver weights were increased only at the 15.6 mg/kg dose. In other studies, nephrotoxicity was noted after 2 weeks of administration of 150 and 450 ppm in the diet, characterized by epithelial hyperplasia of the proximal renal tubules. Ataxia associated with demyelination and fragmentation of femoral nerve fibers also occurred at a dietary level of 1500 ppm. Except for decreased body weights at birth and weaning, no effects on fertility or progeny were found. No porphyrinogenic effects were noted

Lymphoid Tissue and Pathological Influences of Toxicants

Toxicologic pathology plays a crucial role in the identification and interpretation of substance-induced health effects. Histology of lymphoid organs is quite sensitive, although it does not flag every model immunotoxic substance. Subtle interferences of toxic compounds, like transmembrane signaling and cell activation, are often not detectable by conventional histology. The immune system by its very dynamic nature manifests a bandwidth in its morphological picture, hence the 'normal' state can be quite variable. Interspecies- and interstrain-dependent differences in the histophysiology of lymphoid organs should be taken into account, as well as the functional and morphological changes in lymphoid organs during life. Increased susceptibility to immunotoxicants may occur during periods of marked histophysiological changes in lymphoid organs. The high sensitivity at perinatal age for a number of immunotoxicants has received specific attention in immunotoxicity testing. In the interpretation of effects, it should be noted that particular components of lymphoid organs may be decreased in number (suppressed-involuted) or increased (stimulated-expanded), but that does not necessarily reflect the overall effects on the immune system.The chapter addresses the histology of lymphoid organs, including tertiary lymphoid structures. Toxicant-induced pathologies are presented and associated mechanisms of toxicity are discussed

Validation of a modified 28-day rat study to evidence effects of test compounds of the immune system

The toxicology profile of new test compounds is ascertained in repeat-dose toxicity studies with exposure over 4 weeks or 3 months which yield a range between a high dose causing overt toxicity and a low dose with no observable (toxic) effect. In recent years, the immune system has been identified as a target of the direct toxic action of chemicals (Dean et al., 1989). A first step to the EU level to developed a test program to detected undesired effects on the immune system was undertaken in Luxembourg in 1984 (Berlin et al., 1987) . In consequence of this international activity, a number of collaborative studies were initiated. The aim of these studies was to select and validate available testing procedures in a tiered approach to find out their appropriateness of indicating adverse effects on the immune system after exposure to chemicals (Vos and vanLoveren, 1987; Hess et al., 1990). In a collaborative toxicity study initiated and coordinated by the Federal Institute for Health Prot ection of Consumers and Veterinary Medicine, four industrial laboratorys and one independent institute participated. The purpose of this study was to qualify and validate additional investigation (i.e., enhanced pathology, functional tests) within an ordinary subacute toxicity test protocol (Annex V, 67/548/EEC; OECD 407) to identify the effects of chemicals on the immune system during their regular safety evaluation