Chronic Effects on Animals and Humans

Chronic Effects on Animals and Humans, Carcinogenic, and Teratogenic Effects... 

Acute effects in animals and humans resulting from a cesium deficiency or related to high cesium intake have not been reported. A high intake of cesium is rapidly excreted via the kidneys (Yamagata etal., 1966), and consequently no reports have been made on any chronic effects due to stable cesium intake. Neither have any mutagenic, carcinogenic or teratogenic effects of stable cesium been either studied or described. 

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. ... 

Cognitive effects Animais Cognitive effects of nicotine have been observed in several species, including humans. Experimental studies have focused primarily on the effects on attention and memory. Cognitive benefits are seen after both acute and chronic administration (Levin et al. 1992). In experimental animals, nicotine improves learning and memory on a variety of tasks. Conversely, the nicotinic antagonist mecamylamine... 

Studies of effects on animals following acute, intermediate, and chronic dermal exposure to marine diesel fuel and JP-5 fuel provide evidence for dermal absorption (NTP/NIH 1986). Case reports concerning a man who washed his hair with an unknown amount of diesel fuel (Barrientos et al. 1977) and a man who washed his hands with an unspecified diesel fuel over several weeks (Crisp et al. 1979) provide possible evidence for dermal absorption, but effects resulting from inhalation versus dermal exposure could not be distinguished in these cases. No other data on the absorption of fuel oils following dermal exposure in humans or animals were located. 

Acute, Intermediate and Chronic-Duration Exposures. Inhalation exposures in both humans and laboratory animals predominate in the available information on acute, intermediate, and chronic effects of HDl, and will be considered here as a group. Information on laboratory animals describes the direct irritant effects of HDl, which was usually inhaled in large doses (>4 ppm) however, no information on the allergic component of HDl toxicity at low doses, the type of dose most commonly encountered in humans, was provided. Information on acute inhalation exposure of humans may be misleading. In most cases of acute exposure, the workers had been exposed to HDl and HDl prepolymers in their workplace for several months or several years (doses often not available). These workers were then tested with a small dose of either HDl or a product containing HDl with the HDl prepolymers and other organics. 

Neurotoxicity. No histopathological effects on organs and tissues of the neurological systems of animals were found in subchronic and chronic oral studies, but signs of central nervous system toxicity were reported in inhalation, oral, and dermal studies. A battery of tests for neurotoxicity would provide further information of the neurotoxicity in animals, which then might be related to possible neurotoxic effects in humans. 

The NE system mediates various autonomic, neuroendocrine, emotional and cognitive functions. One of the central roles of NE is response to stress and aversion. This role can be summarized as an activation of response to the acute stress and aversion, followed by decreased reaction to repeated or chronic aversion. Since the response to stress and aversion is a basic part in pathology of mood disorder, NE should play an important role in anxiety, depression and mania. Indeed, this role has been demonstrated in numerous animal and human studies. Majority of antidepressant drugs and mood stabilizers affect NE system as their direct or indirect target. Various medications have different effects on NE neuronal activity. The majority of antidepressants, Li and benzodiazepines suppress NE transmission. Other medications, such as AADs, activate NE neuronal firing activity and NE release. Appropriate combination of different medications, based on the consideration of their effect on NE system, might be critical to obtain good treatment outcome. The combination of SSRIs... 

In conclusion, in order to make predictions regarding the safety of the nasal formulation on mucociliary clearance, both in vitro and in vivo studies have to be performed. It is also essential to determine long-term use effects in animals and in humans if the nasal formulation is intended for subchronic or chronic administration. 

Chronic toxicity studies provide information on the long-term health effects of chemical substances. Adverse health effects in exposed animals and subsequent severe damage are known to occur after repeated exposure to low doses over a period of time. The slow accumulation of mercury or lead in the body or after a long latency period from exposure to chemical carcinogens is an example. Chronic or prolonged periods of exposure to chemical substances may also cause adverse effects on the reproduction and behavior of animals and humans. The symptoms caused after chronic exposure usually differ from those observed in acute poisoning from the same chemical. In fact, when exposed to low concentrations of chemical substances, as is the case with chronic toxicity studies, the industrial worker and common public are unaware of the exposure. 

The RfC (reference concentration) method for chronic exposure to gases was proposed by EPA (1994) as an approach to the dosimetry correction for effects on the respiratory system. This method has not been used by the NAC/ AEGL Committee for the following reasons (1) the RfC dosimetry corrections from animal to man are based on theoretical constructs that have not been confirmed and validated with experimental data (2) some of the RfC assumptions are qnestionable and can have a significant impact upon the calculated dosimetry correction between animals and humans. Below is a discussion of two key examples and their impact upon the dosimetry adjustment. The assnmptions are the requirement of uniform deposition in compartments and eqnivalent percent of deposition in animals and humans. 

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