Systemic exposure

Dihydroxybenzenes (DHBs) are slightly more acutely toxic than phenol (Table 5). Contact with dihydroxybenzene through oral, dermal, or respiratory routes can induce significant systemic exposure. Skin or eye effects have been demonstrated during chronic or accidental professional exposure. No systemic effect has been described in such circumstances. 

Trichloroethylene is acutely toxic, primarily because of its anesthetic effect on the central nervous system. Exposure to high vapor concentrations is likely to cause headache, vertigo, tremors, nausea and vomiting, fatigue, intoxication, unconsciousness, and even death. Because it is widely used, its physiological effects have been extensively studied. 

The subtle interaction of air pollutants with these other stressors to plants and vegetation is the subject of ongoing research. For some plant systems, exposure to air pollutants may induce biochemical modifications which interfere with the water balance in plants, thereby reducing their ability to tolerate drought conditions. 

Hydrofluoric acid is highly corrosive to skin and mucous membranes. Even in fairly low concentrations, it causes painful skin burns and severe damage to eyes and the respiratory system. Exposure at higher levels results in destruction of tissues and death. No one in l e.xas City was exposed to more than trace concentrations of hydrofluoric acid. The acid vessel had a capacity of about 850 barrels of which a small fraction was released. 

Industrial environments expose individuals to a plethora of airborne chemical compounds in the form of vapors, aerosols, or biphasic mixtures of both. These atmospheric contaminants primarily interface with two body surfaces the respiratory tract and the skin. Between these two routes of systemic exposure to airborne chemicals (inhalation and transdermal absorption) the respiratory tract has the larger surface area and a much greater percentage of this surface exposed to the ambient environment. Or dinary work clothing generally restricts skin exposures to the arms, neck, and head, and special protective clothing ensembles further limit or totally eliminate skin exposures, but breathing exposes much of the airway to contaminants. 

S3A Note for Guidance on Toxicokinetics The Assessment of Systemic Exposure in Toxicity Studies... 

The most important potential complication of phenol-based peels is cardiotoxicity. Phenol is directly toxic to myocardium. Studies in rats have shown a decrease in myocardial contraction and in electrical activity following systemic exposure to phenol [i6]. Since fatal doses ranged widely in these studies, it seems that individual sensitivity of myocardium to this chemical exists. In humans neither sex/age nor previous cardiac history/blood phenol levels are accurate predictors for cardiac arrhythmia susceptibility [17]. 

The Phase I study explored i.v. administration of BB-83698 at single dose-escalating levels up to 475 mg and systemic exposures were reportedly linear in both animals and humans [84]. While dose-limiting CNS effects... 

Once absorbed, ezetimibe undergoes extensive glucuronida-tion in the intestinal wall to the active metabolite (ezetimibe glucuronide). Ezetimibe and the active metabolite are entero-hepatically recirculated back to the site of action, which limits systemic exposure and may explain the low incidence of adverse effects (Table 9-9). Ezetimibe alone or with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in LFTs. Currently, clinical trials designed to determine ezetimibe s effects on CHD morbidity and mortality have not been completed. The time until maximum effect on lipids for ezetemibe is generally 2 weeks. 

Not altered in advanced age, mild to moderate renal impairment, mild hepatic impairment (Child-Pugh A). Sign, altered in severe renal disease and moderate hepatic impairment (Child-Pugh B) Systemic exposure to duloxetine decreased by V3 in smokers (dose change not recommended) Multiple drug-drug interactions possible with CYP4502D6 and 1A2 substrates/ inhibitors... 

Topical NSAID preparations are used infrequently in North America. Theoretically, administration via a topical vehicle targets the joints involved and decreases systemic exposure. Randomized, controlled trials, typically of less than 4 weeks duration, have suggested that topical NSAIDs are superior to placebo in relieving OA pain in the first 2 weeks of treatment, but the effect may decline over time.33 Moreover, data are lacking to quantify the theoretical safety advantage of administering NSAIDs topically. 

Current guidelines for toxicity evaluation of ophthalmic formulations involve both single and multiple applications, dependent on the proposed clinical use [39]. The multiple applications may extend over a 9-month period and incorporate evaluations of ocular irritation and toxicity, systemic toxicity, and determinations of systemic exposure (toxicokinetics). In many cases the systemic exposure from an ocular route is less than by parenteral administration, information that will assist in determining whether additional studies may be needed to establish systemic safety of the ophthalmic preparation. U.S. and international guidance documents are available [71,72], and regulations and tests have been summarized for ophthalmic preparations [39,73,74],... 

Muck, W., Mai, I., Fritsche, L., Ochmann, K., Rohde, G., Unger, S., Johne, A., Bauer, S., Budde, K., Roots, I., Neumayer, H.-H., Kuhlmann, J., Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporin-treated kidney transplant recipients, Clin. Pharmacol. Ther. 1999, 65, 251— 261. 

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

Effects of TCDD on macrophages have also been examined. When assessed ex vivo, macrophage functions such as tumor cell lysis, phagocytosis and oxidative burst were not suppressed by exposure to TCDD.9396 101 In other experimental systems, exposure to TCDD increases IL-1 and TNF production by macrophages.99 102 103 However, the ability of TCDD to alter IL-1 and TNF production is likely organ- or stimulus-specific, because in the context of respiratory viral infection, exposure to TCDD had no effect on IL-1 or TNF-a levels.80... 

Dearman, R.J., Caddick, H., Basketter, D.A. and Kimber, I., Divergent antibody isotype responses induced in mice by systemic exposure to proteins A comparison of ovalbumin with bovine serum albumin. Food Chem. Toxic., 38, 351, 2000. 

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