Animal studies absorption

Hexachloroethane has been found in the plasma of workers wearing protective clothing and respiratory protection suggesting that hexachloroethane can be absorbed following inhalation and/or dermal exposure. Based on the minimal effects seen on target tissues (liver and kidney) in animal studies, absorption from the lungs seems to be limited. Dermal absorption was also estimated to be low based on calculated dermal penetration rates. 

Absorption of TCE following inhalation exposure in humans is characterized by an initial rate of trichloroethylene uptake that is quite high. Retention of inhaled TCE has been measured at 37% and 75% of the amount inhaled. Absorption of TCE following oral exposure in both humans and animals is rapid and extensive. In animal studies, absorption from the gastrointestinal tract has been measured at 91-98%, and peak TCE blood levels are attained within a matter of hours. Dermal absorption of TCE in both humans and animals is slow, but dermal absorption studies are complicated by the fact that pure liquid TCE can act to defat the skin and thereby enhance its own absorption. 

In animal studies, absorption of vitamin D [102] and E [103] has been shown to depend on the presence of bile salts in the intestine. In rats, a polar lipid, oleic acid, is absorbed almost as well from an emulsion as from a micellar solution while a-tocopherol uptake from an emulsion was much less than from a micellar solution... 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

Children s Susceptibility. No studies were located in which comparisons were made between the sensitivity of children and adults to the toxicity of americium. Animal studies indicate that juvenile dogs are less susceptible than adults to americium-induced bone cancer (Lloyd et al. 1999). No direct evidence was located to indicate that the pharmacokinetics of americium in children may be different from that in adults. Based on dosimetric considerations related to differences in the parameters of available models, as well as studies in animals, it seems likely that children may be more susceptible to americium toxicity than are adults by virtue of age-related differences in pharmacokinetics. Absorption of ingested americium may be as much as 200 times greater in neonatal animals than in adults. (Bomford and Harrison 1986 David and Harrison 1984 Sullivan et al. 1985). 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

These animal studies should indicate to the pharmacist that blood flow can, under certain circumstances, be an important patient variable that may affect the absorption of drugs. Patients in heart failure would generally be expected to have a decreased cardiac output and, therefore, a decreased splanchnic blood flow. This could lead to a decreased rate of absorption for drugs when the blood flow rates in Eq. (7) become rate-limiting. In addition, redistribution of cardiac output during cardiac failure may lead to splanchnic vasoconstriction in patients [57], Other disease states and physical activity can also decrease blood flow to the GIT [2 4], Thus, the pharmacist must be aware of the possible effect of blood flow rate, especially alterations in the rate, on the availability of drugs. 

As described above, it will be normal to assume that the dose interval is 24 hours, i.e., once-a-day dosing. Absorption can be estimated with good confidence from absorption in the rat (see Section 6.1). Clearance is the sum of the predicted hepatic, renal, biliary and extrahepatic clearance. Hepatic clearance can be derived from in vitro studies with the appropriate human system, using either microsomes or hepatocytes. We prefer to use an approach based on that described by Houston and Carlile [83], Renal clearance can be predicted allometrically (see section 6.8.1). The other two potential methods of clearance are difficult to predict. To minimize the risks, animal studies can be used to select compounds that show little or no potential for clearance by these routes. As volume can be predicted from that measured in the dog, after correction for human and dog plasma protein binding (see Section 6.2), it is possible to make predictions for all of the important parameters necessary. 

The minor effects of hexachloroethane on organs other than the lungs in animal studies indicates that absorption does occur, but is probably minimal. Given the lipophilic nature of hexachloroethane, absorption across the lung epithelium is possible. 

In animal studies [9], up to 8% of isotopically labelled mercuric chloride applied to the skin was absorbed within 5 h. The state of the skin is one factor which determines the rate of absorption [10]. Passive diffusion cannot be the only process involved, since the absolute absorption rate of mercury increases with increasing concentration up to a plateau value. In addition, skin absorption probably occurs transepidermally rather than via the follicular pathway [11]. 

A case can often be made to omit studies as scientifically unnecessary, because it is possible to conduct an adequate risk assessment without them. This is most often the case if the substance decomposes to degradants of known hazardous properties. For example the substance may hydrolyse rapidly to non-toxic products, so the key issue is to establish that this happens rapidly in the stomach before the parent substance can be absorbed. There may then be a case for omitting the expensive long-term animal studies, providing it is also established that there is no dermal or inhalation absorption from these exposure routes. In a similar way, it may be justified to omit ecotoxicity studies on a substance which hydrolyses or otherwise decomposes in the aquatic environment to stable products that have already been tested. 

Quantitative data describing the rate of absorption of endrin following inhalation exposure were not available. Cases of occupational exposure reported by Hoogendam and coworkers (1965) and laboratory animal studies reported by Treon et al. (1955) indicate that when endrin is inhaled and absorbed it can produce serious adverse biological effects. 

Bioavailability from Environmental Media. No information was found regarding the absorption of di- -octylphthalate by humans or laboratory animals following inhalation or dermal exposures. No information is available about absorption following oral exposure in humans. However, indirect evidence from animal studies suggests that the compound is readily absorbed by this route (Albro and Moore 1974 Oishi 1990). Additional information is needed on the absorption of di- -octylphthalate as a result of inhalation of contaminated air, ingestion of contaminated food and water, and dermal contact with contaminated soils and sediments. 

Evidence further suggests that male rats eliminate disulfoton at a faster rate than females. This difference may be due to differences in absorption, metabolism, retention, excretion, or a combination of factors. The metabolic pathways of disulfoton are relatively well understood based on data from animal studies (Bull 1965 Lee et al. 1985 March et al. 1957 Puhl and Fredrickson 1975). Similar metabolites have been detected in the urine and tissues from humans exposed to disulfoton (Brokopp et al. 1981 Yashiki et al. 1990). One study suggests that a greater percentage of disulfoton sulfoxide is oxidized to demeton S-sulfoxide, rather than disulfoton sulfone to form demeton S-sulfone (Bull 1965). Additional studies in animals, designed to measure the rate and extent of absorption, distribution, and excretion of disulfoton after inhalation or dermal exposure would be useful for predicting the toxicokinetics of disulfoton in humans at an occupational or hazardous waste site. 

A basic starting point in the development of predictive absorption models is to review the mathematical descriptions of rate and extent of dmg absorption. A physical model for simultaneous fluid flow and intestinal absorption that applies broadly to idealised simulation experiments, animal studies, and in vivo studies in humans has been described by Ho et al. [30] and is depicted in Figure 2.4. 

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