Veterans and Agent Orange: Update 1996

Chapter 3 reviews the results of animal studies published during the past three years that investigated the toxicokinetics, mechanism of action, and disease outcomes of TCDD, plus the herbicides themselves.

TCDD elicits a diverse spectrum of biological sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive/developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. These effects vary according to the age, sex, species, and strain of the animals involved. To date, the scientific consensus is that TCDD is not genotoxic and that its ability to influence the carcinogenic process is mediated via epigenetic events such as enzyme induction, cell proliferation, apoptosis, and intracellular communication.

Recent studies on the effects of TCDD and related substances on the immune system amplify earlier findings and suggest that these compounds affect primarily the T-cell arm of the immune response. Direct effects of TCDD on T cells in vitro, however, have not been demonstrated suggesting that the action of TCDD may be indirect. In contrast, a number of animal studies of the reproductive and developmental toxicity of TCDD suggest that developing animals may be particularly sensitive to the effects of TCDD. Specifically, male reproductive function has been reported to be altered following perinatal exposure to TCDD. In addition, experimental studies of the effects of TCDD in the peripheral nervous system suggest that TCDD can cause a toxic polyneuropathy in rats after a single, low dose. Other recent studies provide evidence that hepatotoxicity of TCDD involves AhR-dependent mechanisms.

The most recent studies have focused on the elucidation of the molecular mechanism of TCDD toxicity. The evidence further supports the concept that the toxic effects of TCDD involve AhR-dependent mechanisms. A better appreciation of the complexity of TCDD effects in target cells has led to the development of refined, physiologically based pharmacokinetic models. These models take into account intracellular diffusion, receptor and protein binding, and liver induction to establish the fractional distribution of the total body burden as a function of the overall body concentration. The association of TCDD with the cytosolic AhR has been shown to require a second protein, known as ARNT, for DNA binding capability and transcriptional activation of target genes. There is also increasing evidence suggesting that events other than receptor binding influence biological response to TCDD. It is now clear that AhR-related signaling influences, and is itself influenced by, other signal transduction mechanisms at low concentrations. Signaling interactions explaining the toxic effects of TCDD may involve growth factors, free radicals, the interaction of TCDD with the estrogen transduction pathway, and protein kinases.

The toxicity of the herbicides used in Vietnam remains poorly studied. In general, the herbicides 2,4-D, 2,4,5-T, cacodylic acid, and picloram have not been identified as particularly toxic substances since high concentrations are often required to modulate cellular and biochemical processes. Impairment of motor function has been reported in rats administered high single oral doses of 2,4-D. The ability of 2,4,5-T to interfere with calcium homeostasis in vitro has been documented and linked to the teratogenic effects of 2,4,5-T on the early development of sea urchin eggs. There is evidence suggesting that both 2,4-D and 2,4,5-T are capable of inducing renal lesions in rats. A series of studies indicates that high concentrations of cacodylic acid results in the formation of a toxic intermediate, the dimethylarsenic radical. No recent studies pertaining to the toxicity of picloram have been published. The half-life in the body of 2,4-D and 2,4,5-T is relatively short and does not appear to extend beyond two weeks. 2,4-D binds covalently to hepatic proteins and lipids, but the molecular basis of this interaction and its biologic consequences are unknown.