Indirect toxicity

The effects of pollution can be direct, such as toxic emissions providing a fatal dose of toxicant to fish, animal life, and even human beings. The effects also can be indirect. Toxic materials which are nonbiodegradable, such as waste from the manufacture of insecticides and pesticides, if released to the environment, are absorbed by bacteria and enter the food chain. These compounds can remain in the environment for long periods of time, slowly being concentrated at each stage in the food chain until ultimately they prove fatal, generally to predators at the top of the food chain such as fish or birds. 

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these mechanisms. 

Indirect toxicity is not so apparent. It most often results from the biotransformation of what may appear to be a relatively unreactive molecule to a highly reactive intermediate, such as an epoxide or a radical species, through Phase 1 metabolism. Occasionally, a Phase 2 (conjugation) step is involved. 

Figure 26.4 Abiotic and biotic interactions leading to the indirect toxicity of chlorofluorocarbons to amphibians. Atmospheric release of chlorofluorocarbons causes the depletion of the stratospheric ozone layer (abiotic-abiotic interaction). Depleted ozone allows for increased penetration of UV-B radiation (abiotic-abiotic interaction). UV-B radiation alone and in combination with fungus (abiotic-biotic interaction) causes increased mortality of amphibian embryos.

Figure 26.5 Indirect toxicity of kraft pulpmill effluent to mosquito fish. Phytosterols in the mill effluent are converted to C19 steroidal androgens through the action of microorganisms in the environment. These androgens masculinize both anatomy and behavior of female mosquito fish. An arrow identifies the modified anal fln on the masculinized female.

Many compounds have been implicated as male reproductive toxicants, but their sites and mechanisms of action are not well understood. The classification of male reproductive toxicants as direct or indirect is useful to help define the primary site of toxicity (Figure 6). A direct toxicant would primarily target the testicular cells, the excurrent duct system of the male reproductive tract, or mature spermatozoa. An indirect toxicant would cause reproductive toxicity by acting on hypothalamic/pituitary neuroendocrine controls or on extragonadal systems. Since the testis is subject to hormonal control and feedback loops, the action of indirect toxicants on endocrine homeostasis can ultimately damage testicular cell types. 

Maternal cocaine use can affect reproduction by adversely affecting the pregnancy. In addition, cocaine use may directly injure the fetus and/or produce behavioral and developmental abnormalities in the neonate. Indirect toxicities of cocaine abuse may result in severe health consequences including child neglect and abuse, loss of family structure, an increased risk of AIDS, and congenitally acquired sexually transmitted diseases (Benowitz 1992). A study of data from 72 U.S. Poison Control Centers in 1990 that analyzed 1.7 million... 

With regard to the toxicity arising from metabolites ( indirect toxicity ), three cases may be distinguished (Figure 33.1) ... 

Effect(s). What were the types of effects observed Did they involve a parent, both parents, or the conceptus/offspring Were they reproductive or developmental What system(s) were involved Were the effects the results of direct or indirect toxicity ... 

Based on the finding that selective expression of PrP in astrocytes is sufficient to restore susceptibility of PrP / mice to scrapie infection, it was advanced that astroglial cells feature in prion disease pathogenesis, possibly by an indirect toxic effect on neurons (Raeber et al, 1997). This hypothesis is supported by an in vitro study where PrP / neurons became susceptible to PrP106-126 neurotoxicity when co-cultured with Prp+/+ astrocytes (Brown, 1999). 

The indirect toxicity of both tangles and plaques almost certainly results from inflammation. Plaques and tangles are recognized as alien by the brain s resident inflammatory cells, the microglial cells, which attempt... 

Besides the effects of the HO2 radical, the indirect toxicity of superoxide may also be due to the fact that superoxide may originate hydroxyl radicals through reaction (23) or even singlet oxygen through reactions (23) and (24) 312, 313) ... 

The direct and indirect toxicity and genotoxicity of particulate matter after its ingestion or inhalation by humans is determined by its physical features such as size, number and surface area of particles, but also by their chemical composition. Elemental carbon and inorganic anions like sulphate and nitrate seem to be the... 

In view of the established multiplicity and possibly far-reaching consequences of effects of ionizing rays, it seems rash to limit the supposed occurrence of toxic substances induced by irradiation to a single compound or a class of substances. Numerous compounds or metabolic processes are likely to be affected. Conclusive comment on the possibility that irradiation induces an abnormal occurrence of substances which have direct or indirect toxic effects, and their actual importance for the pathophysiology of the radiation syndrome will only be possible after a systematic and detailed search for them. 

Indirect toxic trauma arises from the ingestion of contaminated food as in mass food poisoning. Many bacterial toxins act through this route. In deliberate chemical agent release, there is also a risk of ingestion of an aerosolised toxin such as botulinum toxin. 

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