Toxic human studies

No acute-duration inhalation MRL could be derived for chlordecone because no data could be located using this route of exposure. Since there are no animal data that examine gastrointestinal, hematological, respiratory, thyroid, or adrenal effects of acute-duration chlordecone administration, additional studies would be useful to establish chlordecone s toxicity. Human studies for the acute duration are completely lacking therefore, it would be helpful if populations exposed to this substance were carefully monitored in order to better understand the toxic effects of humans exposed to chlordecone. 

The primary objective of a Phase I trial is to assess the safety of the drug in humans. Studies are normally conducted in healthy male volunteers, although specific categories of subject may be used in certain cases. For example, to avoid the risk of low blood pressure, subjects with mild hypertension would be more appropriate for the evaluation of antihypertensive drugs, while patients are likely to be used in the case of drugs that are expected to produce significant toxic effects (e.g. anti-cancer cytotoxic drugs). Remuneration may be offered for participation in the study. The number of subjects is normally between 10 and 100 people. 

GL31 Safety Repeat-dose toxicity test Studies to evaluate the safety of residues of veterinary drugs in human food Repeat-dose toxidly testing... 

Peroxidation of lipids is another factor which must be considered in the safety evaluation of liposome administration. Smith and coworkers (1983) demonstrated that lipid peroxides can play an important role in liver toxicity. Allen et al. (1984) showed that liposomes protected by an antioxidant caused less MPS impairment than liposomes subjected to mild oxidizing conditions. From the study of Kunimoto et al. (1981) it can be concluded that the level of peroxidation in freshly prepared liposome preparations and those on storage strongly depends both on the phospholipid fatty acid composition and on the head group of the phospholipid. Addition of appropriate antioxidants to liposomes composed of lipids which are liable to peroxidation and designed for use in human studies is therefore necessary. 

Shimada, T. et al. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals studies with liver micro-somes of 30 Japanese and 30 Caucasians. /. Pharmacol. Exp. Ther., 270,414-23. 

Mineral Oil Hydraulic Fluids. No human studies examining dermal end points were located. In animals, no information on dermal effects following inhalation or oral exposure were located. A number of mineral oil hydraulic fluids have been tested for acute dermal toxicity in rabbits. Signs of skin irritation have been observed following application of a naphthenic petroleum-based hydraulic fluid designated as MIL-H-5606... 

The identified human studies and the animal studies did not identify the primary target of toxicity for... 

Polyalphaolefin Hydraulic Fluids. No human studies for polyalphaolefin hydraulic fluids were located. Polyalphaolefin hydraulic fluids are used in U.S. military aircraft hydraulic systems thus, there is a potential for occupational exposure. Animal studies were insufficient for determining the primary targets of toxicity. Epidemiology studies examining a number of end points would be useful for identifying targets of toxicity. 

Developmental Toxicity. No studies were located regarding developmental effects in humans following hydrogen sulfide exposure. 

Developmental Effects. Evidence from human studies on congenital anomalies as an end point (Emhart et al. 1985, 1986 McMichael et al. 1986 Needleman et al. 1984) indicate no association between prenatal exposure to low levels of lead and the occurrence of major congenital anomalies. This conclusion is further supported by developmental toxicity studies conducted in rats and mice these studies provide no evidence that lead compounds (acetate or nitrate) are teratogenic when exposure is by natural routes (i.e., inhalation, oral, dermal). Intravenous or intraperitoneal injection of lead compounds (acetate, chloride, or nitrate) into pregnant rats, mice, or hamsters, however, has produced malformations in several studies reviewed by EPA (1986a). 

Developmental Toxicity. Three human studies that described congenital malformations as an end point allow no definitive conclusion to be drawn regarding an association between prenatal lead exposure and the occurrence of congenital anomalies (Emhart et al. 1985, 1986 McMichael et al. 1986 ... 

Human studies including case reports, epidemiological studies, and, in some cases, direct human studies (with volunteers). The advantages of these studies are that toxic effects are evaluated in humans and no interspecies extrapolation is... 

Evidence from rodent, nonhuman primate, and post-mortem human studies indicates that METH is highly toxic to the CNS. This section briefly reviews neurotoxicity associated with METH abuse with particular attention on monoamines. Excellent and detailed reviews have been published elsewhere.77 237-242... 

Reproductive Toxicity. No studies have been conducted in humans regarding reproductive toxicity of acrylonitrile after inhalation, oral, or dermal exposure or inhalation and dermal exposures in animals. Studies in male mice have shown that exposure to acrylonitrile in drinking water affects sperm count and results in tubular degeneration. No effects on male reproductive organs have been reported in... 

Neurotoxicity. Clinical signs indicative of disturbances of the nervous system in exposed humans have been well documented in short-term studies at high doses and appear to be reversible. These effects are characteristic of cyanide toxicity. Animal studies confirm findings in humans. In longer-term studies, effects on the nervous system have also been reported, but it is not certain if these effects are permanent or reversible following termination of acrylonitrile exposure. 

Aniline may be absorbed following inhalation, ingestion, and dermal exposures. The inhalation toxicity of aniline was studied in several animal species, but only one study that utilized multiple exposure concentrations for sublethal effects was located. Data from human studies lack specific details or exposures... 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

Effect of Dose and Duration of Exposure on Toxicity. No studies were located where -hexane concentration was measured in workplace air before workers became ill, so no dose-response relationship can be defined for human neurotoxicity as the result of -hexane exposure. Information on duration of exposure leading to toxicity is available from some case series reports. An occupational exposure caused sensory disturbances in the lower extremities after approximately 2 months (Herskowitz et al. 1971). A case of peripheral neuropathy after 7 months of exposure was reported among press-proofing workers in Taipei (Wang et al. 1986) a serious case resulting in quadriplegia after 8 months of exposure was reported among sandal workers in Japan (Yamamura 1969). Based on case reports, it can be estimated... 

Category Duration of Human Administration Clinical Phase Subacute or Chronic Toxicity Special Studies... 

Legator MS, Ward JB Jr. 1984. Genetic toxicity Relevant studies with animals ahd humans. In Reproduction lie new frontier in occupational and environmental health research. Prog Clin Biol Res 160 491-525. 

Reproductive Toxicity. No studies were located regarding reproductive effects in humans or animals following inhalation or dermal exposure to di-ft-octylphthalate. No studies were located in humans following oral exposure to this compound. Di-u-octylphthalate caused significant decreases in human sperm motility in vitro (Fredricsson et al. 1993). The results of several acute- and intermediate-duration oral studies in rodents indicate that the potential of di-w-octylphthalate to cause adverse reproductive effects is low. Unlike other phthalate esters such as di(2-ethylhexyl)phthalate, di-w-octylphthalate does not appear to adversely affect testicular function or morphology (Foster et al. 1980 Gray and Butterworth 1980 Heindel et al. 

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