Biotransformation chemical exposure

Increased clearance of steroid hormones due to induction of hepatic biotransformation enzymes following chemical exposure often has been cited as a possible mechanism by which toxicants could lower circulating testosterone or 17/3-estradiol levels. While enhanced clearance of sex steroids has been demonstrated following chemical exposure and induction of hepatic biotransformation enzymes, elegant feedback control mechanisms tend to ensure that more hormone is produced and homeostasis is maintained (Figure 17.2). Enhanced clearance of sex steroids can contribute to endocrine disruption if the toxicity also results in impaired hormone synthesis (i.e., gonadal toxicity or interference with the feedback control of hormone synthesis). 2,3,7,8-Tetrachlorodibenzodioxin appears to lower circulating sex steroid levels via this dual effect. 

Individuals within a species must overcome numerous challenges to survive and reproduce, and chemical exposure is simply one of those challenges. Some of the exposed individuals may succumb to the toxin, whereas others may be able to resist. Individuals that remediate against the toxic impacts of chemical pesticides or antibiotics, through biotransformation or other techniques, are more likely to survive and pass their genes along to the next generation. 

Aquatic organisms, such as fish and invertebrates, can excrete compounds via passive diffusion across membranes into the surrounding medium and so have a much reduced need for specialised pathways for steroid excretion. It may be that this lack of selective pressure, together with prey-predator co-evolution, has resulted in restricted biotransformation ability within these animals and their associated predators. The resultant limitations in metabolic and excretory competence makes it more likely that they will bioacciimiilate EDs, and hence they may be at greater risk of adverse effects following exposure to such chemicals. 

The biotransformation of a given chemical compound in experimental animals and in humans may differ. Furthermore, high doses of chemical compounds are used in studies with experimental animals, and this may cause alterations in biotransformation of the tested chemicals that do not occur at the lower doses relevant to the human exposure situation. For example, a metabolic pathway dominating at low doses may become saturated, and a salvage metabolic pathway, e.g., one that produces reactive intermediates of the compound, may become involved in the biotransformation of the chemical. Since this intermediate could never be produced at the exposure levels encountered in humans, the overall result... 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

In vitro exposure is most straightforward for direct immunotoxicants. However, materials that require biotransformation would require special culture systems (e.g., culture in the presence of S9). Furthermore, an additional limitation of in vitro methods would be the physicochemical characteristics of the test material, which may interfere with the in vitro system. Such characteristics may include the need for serum, effects of vehicle on cells (such as DMSO), and chemical binding to cells. In vitro systems do not take into account the interactions of the different components and it is difficult to reproduce in vitro the integrity of the immune system. Finally, in vitro systems do not account for potential neuro-immuno-endocrine interactions. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

Enzyme inhibition. The enzymes of biotransformation may be inhibited by a single exposure to chemicals. This occurs by several mechanisms formation of a complex, competition between substrates, destruction of the enzyme, reduced synthesis of the enzyme, allosteric effects, and lack of cofactors. The consequences will depend on the role of metabolism in toxicity in the same way as induction (see above). 

The rate of biotransformation of a chemical depends on the amount and efficiency of the pertinent biotransformation enzymes. Enzyme activity is partly genetically determined but may also vary between and within people because of enzyme induction caused by previous exposure to the same or related chemicals. Variation in enzyme activity may also be caused by enzyme inhibition due to concurrent exposures. 

A factor common to each of these processes is that substances must past through one or more cellular membranes. Small, lipophilic molecules are the substances that pass most easily through such membranes. The key connection here is that the chemical properties that are desirable in solvents require them to be composed of small, lipophilic molecules. Thus, solvents are some of the most easily absorbed and distributed in the body. However, the most easily excreted substances are those that are water soluble. Thus, the solvents relative inertness results in storage in the body rather than in biotransformation, which in turn prevents elimination from the body. Prolonged exposure to solvents, therefore, can result in the accumulation of a toxic concentration of that substance. This example is one of many in science in which properties that are desirable for one purpose can be detrimental for others. 

These examples show that also in the case of single chemicals, such as pesticides and metals, exposure assessment should not only focus on the parent chemical but also include the metabolites and transformation products produced either in the environment or upon biotransformation in the organism. 

Humans are exposed continuously and unavoidably to a myriad of potentially toxic chemicals that are inherently lipophilic and, consequently, very difficult to excrete. To effect their elimination, the human body has developed appropriate enzyme systems that can transform metabolically these chemicals to hydrophilic, readily excretable, metabolites. This biotransformation process occurs in two distinct phases. Phase I and Phase II, and involves several enzyme systems, the most important being the cytochromes P450. The expression of these enzyme systems is regulated genetically but can be modulated also other factors, such as exposure to chemicals that can either increase or impair activity. Paradoxically, the same xenobiotic-metabolizing enzyme systems also can convert biologically inactive chemicals to highly reactive intermediates that interact with vital cellular macromolecules and elicit various forms of toxicity. Thus, xenobiotic metabolism does not always lead to deactivation but can result also in metabolic activation with deleterious consequences. 

Liver damage caused by toxic substances sometimes only appears and is hence first recognizable after a latent period of several years. This applies particularly to radioactive substances (e.g. thorotrast, which has a latent period of up to 40 years). Exogenous factors (alcohol, medicaments and chemicals) can substantially impair the course and prognosis of intoxication. This may be due to (1.) acute multiple intoxication by simultaneous exposure to various toxic substances or (2.) the fact that the noxa is administered during the deficiency period of a biotransformative induction, since toxic substances cause greater hepatic lesions in this phase. 

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