Toxicodynamics

Toxicodynamics, termed pharmacodynamics in pharmacology, describes the dynamic interactions of a toxicant with a biological target and its biological effects. A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other receptors. When a toxicant enters an organism, it can interact with these receptors and produce structural or functional alterations. The mechanism of action of the toxicant, as determined by a toxicant’s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level. Toxicodynamics, termed pharmacodynamics in pharmacology, describes the dynamic interactions of a toxicant with a biological target and its biological effects. A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other receptors. When a toxicant enters an organism, it can interact with these receptors and produce structural or functional alterations. The mechanism of action of the toxicant, as determined by a toxicant’s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level. Toxicants have been grouped together according to their chemical properties by way of quantitative structure-activity relationships (QSARs), which allows prediction of toxic action based on these properties. endocrine disrupting chemicals (EDCs) and carcinogens are examples of classes of toxicants that can act as QSARs. EDCs mimic or block transcriptional activation normally caused by natural steroid hormones. These types of chemicals can act on androgen receptors, estrogen receptors and thyroid hormone receptors. This mechanism can include such toxicants as dichlorodiphenyltrichloroethane (DDE) and polychlorinated biphenyls (PCBs). Another class of chemicals, carcinogens, are substances that cause cancer and can be classified as genotoxic or nongenotoxic carcinogens. These categories include toxicants such as polycyclic aromatic hydrocarbon (PAHs) and carbon tetrachloride (CCl4). The process of toxicodynamics can be useful for application in environmental risk assessment by implementing toxicokinetic-toxicodynamic (TKTD) models. TKTD models include phenomenas such as time-varying exposure, carry-over toxicity, organism recovery time, effects of mixtures, and extrapolation to untested chemicals and species. Due to their advantages, these types of models may be more applicable for risk assessment than traditional modeling approaches. While toxicokinetics describes the changes in the concentrations of a toxicant over time due to the uptake, biotransformation, distribution and elimination of toxicants, toxicodynamics involves the interactions of a toxicant with a biological target and the functional or structural alterations in a cell that can eventually lead to a toxic effect. Depending on the toxicant’s chemical reactivity and vicinity, the toxicant may be able to interact with the biological target. Interactions between a toxicant and the biological target may also be more specific, where high-affinity binding sites increase the selectivity of interactions. For this reason, toxicity may be expressed primarily in certain tissues or organs. The targets are often receptors on the cell surface or in the cytoplasm and nucleus. Toxicants can either induce an unnecessary response or inhibit a natural response, which can cause damage. If the biological target is critical and the damage is severe enough, irreversible injury can occur first at the molecular level, which will translate into effects at higher levels of organization. EDCs are generally considered to be toxicants that either mimic or block the transcriptional activation normally caused by natural steroid hormones. These chemicals include those acting on androgen receptors, estrogen receptors and thryoid hormone receptors. Endocrine disrupting chemicals can interfere with the endocrine system in a number of ways including hormone synthesis, storage/release, transport and clearance, receptor recognition and binding, and postreceptor activation. In wildlife, exposure to EDCs can result in altered fertility, reduced viability of offspring, impaired hormone secretion or activity and modified reproductive anatomy. The reproductive anatomy of offspring can particularly be affected if maternal exposure occurs. In females, this includes mammary glands, fallopian tubes, uterus, cervix, and vagina. In males, this includes the prostate, seminal vesicles, epididymitis and testes. Exposure of fish to EDCs has also been associated with abnormal thyroid function, decreased fertility, decreased hatching success, de-feminization and masculinization of female fish and alteration of immune function. Endocrine disruption as a mode of action for xenobiotics was brought into awareness by Our Stolen Future by Theo Colborn. Endocrine disrupting chemicals are known to accumulate in body tissue and are highly persistent in the environment. Many toxicants are known EDCs including pesticides, phthalates, phytoestrogens, some industrial/commercial products, and pharmaceuticals. These chemicals are known to cause endocrine disruption via a few different mechanisms. While the mechanism associated with the thyroid hormone receptor is not well understood, two more established mechanisms involve the inhibition of the androgen receptor and activation of the estrogen receptor. Certain toxicants act as endocrine disruptors by interacting with the androgen receptor. DDE is one example of a chemical that acts via this mechanism. DDE is a metabolite of DDT that is widespread in the environment. Although production of DDT has been banned in the Western world, this chemical is extremely persistent and is still commonly found in the environment along with its metabolite DDE. DDE is an antiandrogen, which means it alters the expression of specific androgen-regulated genes, and is an androgen receptor (AR)-mediated mechanism. DDE is a lipophilic compound which diffuses into the cell and binds to the AR. Through binding, the receptor is inactivated and cannot bind to the androgen response element on DNA. This inhibits the transcription of androgen-responsive genes which can have serious consequences for exposed wildlife. In 1980, there was a spill in Lake Apopka, Florida which released the pesticide dicofol and DDT along with its metabolites. The neonatal and juvenile alligators present in this lake have been extensively studied and observed to have altered plasma hormone concentrations, decreased clutch viability, increased juvenile mortality, and morphological abnormalities in the testis and ovary.