Chemical dose level

Similar results for the case in which the metabolite M is the carcinogenic entity are shown in Table II. In this case the predicted response may be either under-estimated or over-estimated when it is based on the observed response at dose levels exceeding the pharmacokinetic threshold. However, as is the case with the parent chemical, dose levels below the pharmacokinetic threshold are proportional to the concentration of the metabolite in the body, and can be used to predict the response at even lower levels. 

Polymers. Ion implantation of polymers has resulted in substantial increases of electrical conductivity (140), surface hardness (141), and surface texturing (142). A four to five order of magnitude increase in the conductivity of polymers after implantation with 2 MeV Ar ions at dose levels ranging from 10 -10 ions/cm has been observed (140). The hardness of polycarbonate was increased to that of steel (141) when using 1 MeV Ar at dose levels between 10 -10 ions/cm. Conductivity, oxidation, and chemical resistance were also improved. Improvements in the adhesion of metallizations to Kapton and Teflon after implantation with argon has been noted (142). 

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-... 

Traditionally, boiler house operational duties include the monitoring of day tank chemical treatment levels and the top-up of additional chemicals as required. Also required is the checking of consumable inventory stock levels and the inspection of chemical feed pumps, injection points, automatic controllers, and other items of dosing and control equipment. 

It thus becomes necessary to preempt the problem by tightly controlling the FW pH, temperature, and residual hardness levels where MU water source contains a high silica level (say, over 20-30 ppm Si02). The location of FW line chemical injection points and the type of chemicals dosed also may influence the risk of silicate sludges and scales developing, and these factors may also need to be considered. 

In the male offspring whose treatment was continued through 11-12 weeks of age, however, dose-related effects were seen on all the above end points, and these effects were significantly different from controls at all three dose levels (Desi et al. 1998) (see also Section S.2.2.4). The study did not determine the critical period (if any) and duration of exposure for these neurological effects. A limitation of this study is that results specifically for methyl parathion were shown only for the somatosensory electrocortico-gram the other results for this chemical were stated in the text, but not shown. 

In a case-control study of pesticide factory workers in Brazil exposed to methyl parathion and formulating solvents, the incidence of chromosomal aberrations in lymphocytes was investigated (De Cassia Stocco et al. 1982). Though dichlorodiphenyltrichloroethane (DDT) was coformulated with methyl parathion, blood DDT levels in the methyl parathion-examined workers and "nonexposed" workers were not significantly different. These workers were presumably exposed to methyl parathion via both inhalation and dermal routes however, a dose level was not reported. The exposed workers showed blood cholinesterase depressions between 50 and 75%. However, the baseline blood cholinesterase levels in nonexposed workers were not reported. No increases in the percentage of lymphocytes with chromosome breaks were found in 15 of these workers who were exposed to methyl parathion from 1 week to up to 7 years as compared with controls. The controls consisted of 13 men who had not been occupationally exposed to any chemical and were of comparable age and socioeconomic level. This study is limited because of concomitant exposure to formulating solvents, the recent history of exposure for the workers was not reported, the selection of the control group was not described adequately, and the sample size was limited. 

The consequences of an increase in the cycles of concentration are that as the level of dissolved solids increases, corrosion and deposition tendencies also increase. The result is that, although increasing the cycles of concentration decreases the water requirements of the cooling system, the required amount of chemical dosing also increases. 

In order to extrapolate laboratory animal results to humans, an interspecies dose conversion must be performed. Animals such as rodents have different physical dimensions, rates of intake (ingestion or inhalation), and lifespans from humans, and therefore are expected to respond differently to a specified dose level of any chemical. Estimation of equivalent human doses is usually performed by scaling laboratory doses according to observable species differences. Unfortunately, detailed quantitative data on the comparative pharmacokinetics of animals and humans are nonexistent, so that scaling methods remain approximate. In carcinogenic risk extrapolation, it is commonly assumed that the rate of response for mammals is proportional to internal surface area... 

MONKEY, Macaca fascicularis 1 or 10 mg/kg BW of trans-chlordane given once weekly for 5 weeks by subcutaneous injection. Adipose tissue, blood, and skin lipids analyzed for up to 20 weeks after the last injection trans-Chlordane and oxychlordane were detected in all tissues. In blood and adipose tissue, trans-chlordane decreased rapidly and oxychlordane increased gradually until a plateau was reached. Good correlations were determined for all chemicals between blood and adipose tissue, regardless of collection time and dose level, and between skin lipids and adipose tissue. At the high dose, trans-chlordane reached a maximum of 35 mg/kg FW in adipose tissue, but was not detectable after 20 weeks. The oxychlordane concentration in adipose tissue of the high-dose group was 25 mg/kg FW after the last injection, and 18 mg/kg FW after 20 weeks (Sasaki et al. 1992)... 

Fenvalerate inhibits intercellular communication between fibroblast cells and enhances the development of hepatocyte foci in rat liver at nonhepatotoxic dose levels. Chemicals that possess these properties are likely to be tumor promoters (Flodstrom et al. 1988). Fenvalerate alone induced no hepatotoxic effects in rat liver, as judged by transaminase activities and histology. However, some rats that were partially hepatectomized and insulted with nitrosodiethylamine — a carcinogen and tumor initiator — had significantly elevated numbers of liver foci after administrations of fenvalerate. This response suggests that fenvalerate is a potential tumor promoter (Flodstrom et al. 1988). 

Cytotoxicity. The liver is the primary target organ for a variety of drugs and chemicals (Hasemen et ah, 1984 Farland et ah, 1985). The prevalence of drug-and chemical-induced liver injury is of concern because some xenobiotics can produce liver damage at dose levels that are magnitudes below that which causes cell death (Plaa, 1976). Environmental and commercial chemicals can increase this effect by as much as 100-fold (Plaa and Hewitt, 1982 Plaa, 1976). Studies of early cell injury caused by exposure to a toxicant can be undertaken easily in monolayer cultures of hepatocytes, whereas early cell injury is very difficult to assess in vivo. 

The PBPK model development for a chemical is preceded by the definition of the problem, which in toxicology may often be related to the apparent complex nature of toxicity. Examples of such apparent complex toxic responses include nonlinearity in dose-response, sex and species differences in tissue response, differential response of tissues to chemical exposure, qualitatively and/or quantitatively difference responses for the same cumulative dose administered by different routes and scenarios, and so on. In these instances, PBPK modeling studies can be utilized to evaluate the pharmacokinetic basis of the apparent complex nature of toxicity induced by the chemical. One of the values of PBPK modeling, in fact, is that accurate description of target tissue dose often resolves behavior that appears complex at the administered dose level. 

Dose-response characterisation. Different chemicals will be associated with different toxicological end-points and the risk of any individual experiencing toxicity is related to the dose that they receive. Very often it is possible to identify a dose level below which the probability of anyone experiencing an adverse effect is veiy low or zero. For additives this is usually referred to as the Acceptable Daily Intake (ADI). 

No studies were located regarding reproductive effects in animals after dermal exposure to mirex. The only animal study that referred to reproductive effects following dermal exposure to chlordecone was conducted in rabbits by Allied Chemical. This study was not available for review. A published review of the study (Epstein 1978) indicated that chlordecone applied to shaved skin at dose levels of 5 or 10 mg/kg for 8 hours/day, 5 days/week, for 3 weeks induced testicular atrophy in two of six rabbits at 5 mg/kg and in one of six rabbits at 10 mg/kg. No other toxic effects were noted. This study is limited by the lack of dose response and lack of a NOAEL for the effect observed. 

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