International Journal of Toxicology

This short article emphasizes the necessity for occupational health physicians to pay closer attention to global environmental issues including risk assessment and risk management of those issues. Industrialization casts both light and shadow. Every effort should be made to balance the light and shadow, and where possible, to provide more of the former and lessen the latter. More experts in this field must be trained and hired as faculty at schools of medicine, particularly at schools or institutes offering training in occupational health.

Systemic studies have been completed in Japan to detect those chemicals in the environment that act as promoters. Well-established two-stage models for liver, stomach, kidney, pancreas, and skin carcinogenesis were employed to detect the promoting effect of Zn Cl₂, Cr Cl₂, Cd Cl₂, Ni Cl₂, and Hg Cl₂. As a result, Ni Cl₂ was found to act as a promoter in renal carcinogenesis.

The theory that all carcinogens are mutagens has been disproved. Numerous nongenotoxic mechanisms are implicated in carcinogenesis. It is inconceivable that a single simple short-term test can be developed to predict nongenotoxic carcinogenicity. Pro longed disturbance of physiological and/or hormonal status may predispose to increased cancer risk. Overnutrition leads to a variety of physiological and hormonal disturbances in rats. It also predisposes to the early onset of ageing-related diseases and the development of a wide variety of benign and malignant neoplasms. It is suggested that overnutrition is associated with increased endogenous generation of electrophiles, which, on the one hand, age cells and tissues, and on the other, overwhelm the normally efficient DNA repair mechanisms. It is further suggested that hormones predispose to cancer by stimulating cellular proliferation and metabolic rate in target tissues. Thus, nongenotoxic mechanisms of carcinogenesis do involve DNA damage, but do so as a late stage rather than as a first event. The two-stage theory of carcinogenesis is misleading in this respect. Careful studies of the relationships between ageing and cancer risks are long overdue.

The pulmonary macrophage provides a critical function in the maintenance of the sterility and integrity of the lung. Inhaled particle deposited in the deep lung may interact directly with macrophages to manifest either primary cellular toxicity or secondary pulmonary damage resulting from impaired macrophage function. The advantages and disadvantages of in vitro macrophage culture systems as predictors of in vivo pulmonary toxicity are briefly described. Recommendations are presented for areas of additional research as well as effective utilization of this assay system.

Much recent data supports the “uptake-reduction” model explaining the carcinogenicity of chromium(VI) compounds and the lack of carcinogenicity of chromium(III) com pounds. Cr(VI) readily enters cells by diffusion through a nonspecific anion channel, whereas cells are relatively impermeable to Cr(III). Glutathione appears to facilitate Cr(VI) uptake by reducing Cr(VI) to Cr(III) after it enters the cell, presumably keeping intracellular Cr(VI) concentration low and allowing for further Cr(VI) uptake. Some other nonenzymatic factors, for example, ascorbate and riboflavin, as well as enzymes, such as cytochrome P-450, DT-diaphorase, and the mitochondrial electron transport chain complexes, are capable of reducing Cr(VI) in vitro, but their contribution in vivo is not clear. Cr(VI), once reduced intracellularly, produces various forms of DNA damage including DNA interstrand crosslinks, DNA-protein crosslinks, DNA strand breaks, and Cr-DNA adducts. The pathway of Cr(VI) metabolism in different tissues appears to influence the type of “reactive intermediates” produced, for example, Cr(V) and radical species, and thus the nature and extent of DNA damage. This DNA damage presumably accounts for observed functional changes in DNA replication and transcription which may be crucial to the carcinogenicity of chromium(VI) compounds.

Zinc is an indispensable trace element and is a constituent of more than 200 enzymes. It can assure the stability of biological molecules such as DNA, or biological structures such as membranes or ribosomes. It is not surprising, therefore, that, compared with zinc toxicity, zinc deficiency is a much more frequent risk. Few acute toxic effects have been ascribed to zinc and no long-term effects were found after single or prolonged exposure at doses below 1 g/kg of food. Zinc is neither mutagenic nor carcinogenic, although its levels may influence tumor growth. Zinc appears not to be teratogenic but, on the contrary, deleterious action on zinc deficiency on the developing organisms is well documented.

New findings on the environmental fate of Hg indicate that lakes can be contaminated by long distance transport on mercury vapor in the atmosphere and that higher levels of Me Hg in fish are associated with acidification of lakes and with the creation of hydroelectric reservoirs. Considerable progress has been made in the understanding of the disposition and metabolism of mercury in the body. Inhaled mercury vapor rapidly enters cells in view of its lipid solubility. Inside the cell, it is oxidized by the enzyme, catalase, to inorganic divalent mercury. The latter may be the proximate toxic species. Me Hg also crosses cell membranes rapidly but, in this case, probably by forming water-soluble complexes whose structures mimic those of endogenous substrates that are transported on specific carriers.

The mechanism of damage to the central nervous system by mercury vapor is still unknown. The kidney damage probably arises from the effect of inorganic mercury on immunocompetent cells causing them to produce antibodies that affect the glomerulus. The selective damage by Me Hg to specific anatomical areas of the brain and the long latent period are still unexplained. Most studies have focused on the earliest biochemical lesion, the inhibition of protein synthesis. Prenatal damage occurs in all areas of the developing brain. Cell division and abnormal neuronal migration are the processes primarily affected. The destruction of microtubules in neuronal and astrocystic cells offers a plausible explanation of the deranged cytoarchitecture. Prenatal effects such as delays in the normal development of prenatally exposed infants occur at exposures substantially lower than those associated with the onset of adult poisoning.

There have been a number of new and exciting advances in the understanding of arsenic toxicity. Organic trivalent arsenicals have been the drug of choice in the treatment of African trypanosomes, the cause of sleeping sickness. In the past, various mechanisms have been proposed for their mode of action in the treatment of this parasitic disease. It now appears that these arsenicals form an adduct with N ^1,-N⁸(glutathionyl)spermidine which inhibits trypanothione disulfide reductase. This enzyme in conjunction with a nonenzymatic reaction is responsible for the maintenance of the required intracellular levels of GSH and perhaps other thiols in African trypanosomes. The primary targets of As³⁺ in mammalian systems are pyruvate dehydrogenase, thiolase, and glutathione reductase. Even though it appears that pyruvate dehydrogenase is the most sensitive target, the net result of these inhibitions is a decreased gluconeogenesis that should be taken into account when treating arsenic poisoning. Although these advances have been made in the understanding of arsenic toxicity, virtually no progress has been made in understanding the biochemical mechanism of action of arsine, probably the deadliest of all arsenic compounds. This lack of progress is disappointing as well as worrisome since arsine is one of the important starting materials in the newer high tech industries. There have been, however, advances made in the treatment of arsenic toxicity. Meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-l-sulfonic acid are orally effective, dithiol chelating agents useful for treating arsenic poisoning. DMSA is an orphan drug for which a New Drug Application has been filed.

Review of the scientific advances in beryllium toxicology during the 1980s in the categories of toxicokinetics, toxicodynamics, experimental pathology, clinical diagnosis, and cancer epidemiology.

Metallothioneins (MTs) are cysteine-rich metal-binding proteins. These proteins play a pivotal role in heavy metal homeostasis and have been widely studied by biochemists, toxicologists, nutritional scientists, and molecular biologists. It is well established that MTs are inducible proteins. They are normally synthesized at low basal levels, but exposure to a wide variety of heavy metals and many organic compounds will dramatically increase synthesis of MTs. This paper summarizes MT induction by reviewing the chemicals that induce these proteins, the molecular mechanism involved in this induction, and the relationship between MT induction and biological function.