Toxic materials biotransformation

The biotransforming pathways are subject to manipulation and modification in a variety of ways. Drug metabolism also depends on age and sex. Drag metabolism may also produce toxic materials. 

A consequence of this hindrance to elimination of toxic materials by complex organisms was the development of specialized routes of elimination. These routes generally evolved in concert (i.e., co-evolved) with biotransformation processes that render chemicals amenable to these modes of elimination (see Chapters 7-9). 

It should not be forgotten that a great deal of biotransformation does occur, especially for metals such as mercury and for many organics. In many cases, the result is a less toxic form of the original input, but occasionally more toxic materials are created. 

It is important to appreciate that the magnitude of the absorbed dose, the relative amounts of bio transformation product, and the distribution and elimination of metaboUtes and parent compound seen with a single exposure, may be modified by repeated exposures. For example, repeated exposure may enhance mechanisms responsible for biotransformation of the absorbed material, and thus modify the relative proportions of the metaboUtes and parent molecule, and thus the retention pattern of these materials. Clearly, this could influence the likelihood for target organ toxicity. Additionally, and particularly when there is a slow excretion rate, repeated exposures may increase the possibiUty for progressive loading of tissues and body fluids, and hence the potential for cumulative toxicity. 

Absorption of a mycotoxin will occur when it crosses body membranes and enters the blood stream. The primary sites of mycotoxin absorption are the gastrointestinal tract (ingestion of contaminated food), lungs (inhalation of contaminated particles or toxin-containing fungal spores) and the skin (direct contact with contaminated materials or pure mycotoxins). When the mycotoxin enters the blood it is then available for distribution. Livers and kidneys have a high capacity to bind many mycotoxins while other mycotoxins are highly lipophilic and can concentrate in body fat. In the final outcome a toxic response by a mycotoxin will be critically influenced by the rate of absorption, distribution, biotransformation and excretion (Smith et al., 1994). 

The primary function of the kidneys is to rid the body of waste materials that are either ingested or produced by metabolism, and to control the volume and composition of the body fluids. The toxins absorbed by the different routes are biotransformed and enter the blood. They are then eliminated through the urine, feces, and air. Since the kidneys receive approximately a quarter of the cardiac output, it is an important organ for the exposure of toxicants and their metabolites. Recent incidents of pet food toxicity and diethylene glycol toxicity indicate that contamination of animal and human food and drugs, respectively, can lead to severe mortahty and morbidity as a result of renal toxicity. 

A toxicant must be present at its cellular site of action in sufficient amounts to exert its deleterious effects. When the concentration is too small it is said that the threshold has not been reached therefore, the material does not exert any adverse action. The distribution of active substances in the body is not uniform, and certain cells can exhibit preferentially high affinities for particular agents. Pharmacokinetic thresholds determine the effective dose of a chemical at its biological target site based on the absorption, distribution, biotransformation, and excretion of the particular chemical. 

A great deal can occur to a xenobiotic between its introduction to the environment and its interaction at the site of action. Many materials are altered in specific ways depending upon the particular chemical characteristics of the environment. Bioaccumulation, the increase in concentration of a chemical in tissue compared to the environment, often occurs with materials that are more soluble in lipids and organics (lipophilic) than in water (hydrophilic). Compounds are often transformed into other materials by the various metabolic systems that reduce or alter the toxicity of materials introduced to the body. This process is biotransformation. Biodegradation is the... 

Two chapters in Casarett and Doull s Toxicology (op. cit.), Distribution, Excretion, and Absorption of Toxicants (C.D. Klaassen) and Biotransformation of Toxicants (I.G. Sipes and A.J. Gandolfi) get to the details of how chemicals move in, around, and out of the body, and of how they are metabolized when in it. Unfortunately, most of this material requires fairly advanced understanding of biology and organic chemistry. 

In vitro exposure is most straightforward for direct immuno-toxicants. However, materials that require biotransformation would require special culture systems (e.g., culture in the presence of S9). 

The whole-cell biocatalysis approach is typically used when a specific biotransformation requires multiple enzymes or when it is difficult to isolate the enzyme. A whole-cell system has an advantage over isolated enzymes in that it is not necessary to recycle the cofactors (nonprotein components involved in enzyme catalysis). In addition, it can carry out selective synthesis using cheap and abundant raw materials such as cornstarches. However, whole-cell systems require expensive equipment and tedious work-up because of large volumes, and have low productivity. More importantly, uncontrolled metabolic processes may result in undesirable side reactions during cell growth. The accumulation of these undesirable products as well as desirable products may be toxic to the cell, and these products can be difficult to separate from the rest of the cell culture. Another drawback to whole-cell systems is that the cell membrane may act as a mass transport barrier between the substrates and the enzymes. 

Army. 1984f. The anaerobic biotransformation of RDX, HMX, and their acetylated derivatives. Technical report NATICK/TR-85/007. Aberdeen Proving Ground, MD U.S. Army Toxic and Hazardous Materials Agency. Document no. AD-A149 464. (authored by McCormick NG et al.)... 

The development of procedures for the isolation of hepatocytes from livers of different species, including man, have allowed the use of this model for comparative studies on the species-related biotransformation and toxicity of xenobiotics. In vitro studies with aflatoxin Bj showed that rat hepatocytes were more sensitive than those from mice, as became apparent by the death of the cells at much lower concentrations, the much higher levels of binding of metabolites of aflatoxin B1 to TCA-precipitable cell-material 33, 34), and the much higher levels of unscheduled DNA-synthesis (55). In addition, the mycotoxin caused segregation of nucleolar components in rat hepatocytes, but not in cells from mice 36). 

Total penetration of the sum of parent compound and metabolite(s) observed with viable skin may be similar to the penetration of the unmetabolized parent compoimd through nonviable skin. The primary barrier to skin absorption is oftrai the nonliving stramm comeum layer on the surface of skin, and metabolism occurs after the rate-limiting step of penetration. The need to maintain viability of skin may be limited to instances when significant biotransformation of test compound in skin occurs. A safety assessment may inaccurately estimate either local or systemic toxicity of a compoimd if it fails to observe significant activation or detoxification of this material in skin. 

To further validate the treatment technology, the contaminated groundwater was subjected to tests for toxicity and teratogenicity before and after treatment (sampled before carbon treatment). As determined by Microtox , embryonic Menidia beryllina, Mysydopsis bahia, and Ceriodaphnia dubia bioassays, these indicators of potential threat to human health and the environment were significantly reduced. This data shows that the treatment system was effective in removing the hazardous properties of the waste material, while simultaneously demonstrating that no metabolic byproducts or toxic intermediates were created by the microbial biotransformation of the waste constituents. 

Since monoterpenoids, in general, show characteristic odor and taste, they have been nsed as cosmetic materials food additives and often for insecticides, insect repellents, and attractant drngs. In order to obtain mnch more fnnctionalized substances from monoterpenoids, various chemical reactions and microbial transformations of commercially available and cheap synthetic monoterpenoids have been carried out. On the other hand, insect larva and mammals have been used for direct biotransformations of monoterpenoids to study their fate and safety or toxicity in their bodies. 

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