Chronic systemic toxicity

EPA. 1991a. Reportable quantity for chronic systemic toxicity and potential carcinogenicity of 4,6-dinitro-o-cresol. ECAO-CIN-R117A. Cincinnati, OFI U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office. 

The tests to be performed to assess both efficacy and toxicity of drugs are highly regulated in the EU, as in most countries in the world. The EU rules and regulations governing medicinal products are compiled in a ten-volume legislation called Eudralex available from the website of the EC (http //ec.europa.eu/health/ documents/eudralex/index en.htm). Specific requirements on acute and chronic systemic toxicity testing of pharmaceuticals are addressed later in this chapter. 

Chronic Systemic Toxicity (Repeated-Dose Toxicity)... 

Chronic systemic toxicity Repeated and prolonged exposure to PPD is believed to increase the risk of non-Hodgkin s lymphomas and multiple myeloma and cancer of the bladder [31-32]. Hair dye formulations containing PPD was incriminated in the increased risk of systemic lupus erythematosus (SLE) and breast cancer, however other studies, showed that there is no significant relationship [33-34]. Aplastic anemia due to PPD exposure also has been reported [35]. 

CHRONIC HEALTH RISKS evidence of chronic systemic toxicity is inconclusive chronic allergen. 

Polyalphaolefin Hydraulic Fluids. Because no chronic-duration human or animal inhalation, oral, or dermal exposure studies using polyalphaolefin hydraulic fluids were located, chronic-duration inhalation or oral MRLs could not be derived. Systemic toxicity studies in which animals were exposed via inhalation, oral, and dermal routes would be useful in identifying the end points of toxicity for humans living at or near hazardous waste sites and exposed for chronic durations. Further carcinogenicity studies on individual organophosphate ester components of hydraulic fluids maybe useful. 

In patients who require chronic systemic corticosteroids for asthma control, the lowest possible dose should be used. Toxicities may be decreased by alternate-day therapy or high-dose inhaled corticosteroids. 

The clinical benefits of systemic corticosteroid therapy in the chronic management of COPD are often not evident, and there is a high risk of toxicity. Consequently, chronic, systemic corticosteroids should be avoided if possible. 

The database for HFC-134a is extensive it contains studies with both human subjects and animal models. Potentially sensitive populations, including patients with COPD and adult and pediatric asthmatic patients, were tested with direct inhalation of HFC-134a from metered-dose inhalers. The response of these groups was no different than that of healthy adults. The 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 metabolism of HFC-134a is well understood, and the relationship of exposure con... 

In a second experiment (Hanhijarvi, Nevalainen, and Mannisto, 1985), the chronic, cumulative dermal effects of anthralin chemicals were studied in minipigs. Using only 12 animals, they were able, by having 32 sites per animal, to study the effects of two different chemicals (dithranol and butantrone both anthralins) in three different formulations at three different concentrations each. The protocol also included observations for systemic toxicity, clinical laboratory measurements, plasma drug analyses, and gross and histopathological examinations. 

In the section that follows, data needs are identified for cyanide forms for which toxicity data were available and were, therefore, summarized in Section 2.2. These forms include primarily sodium cyanide, potassium cyanide, and hydrogen cyanide. As seen from Figure 2-6, information is available regarding death, systemic effects of acute exposure, and neurological effects in humans after inhalation, oral, and dermal exposure to cyanide. In addition, information is available regarding chronic systemic effects in humans after inhalation and oral exposure. 

Neurological Effects. Neurological effects in hrnnans after acute inhalation exposure to chloroform are well documented because chloroform has been used as an anesthetic for surgery. Inhaled chloroform acts as a depressant on the central nervous system. Chronic inhalation exposure to chloroform resulted in exhaustion, lack of concentration, depression, and irritability in occupationally exposed people (Challen et al. 1958). In a case study, chloroform inhalation for 12 years resulted in psychotic episodes, hallucinations, and convulsions (Heilbmnn et al. 1945). Central nervous system toxicity was observed in humans after oral exposure to chloroform, which suggests that the effects of inhalation and oral exposure are similar. In case reports of patients who intentionally or accidentally ingested several ounces of chloroform, deep coma with abolished reflexes occurred within a few minutes (Piersol et al. 1933 Schroeder 1965 Storms 1973). 

Another model, used in the USA, is the OASYS Pollution Prevention Optional Analysis System, developed by the Toxic Use Reduction Institute. Technologies are assessed on a variety of hazard criteria, including acute and chronic human toxicity, physical properties, aquatic impacts, persistence/bioaccumulation, atmospheric releases, disposal, chemical properties, energy/resource use, product hazard and exposure potential. Alternatives are rated to... 

The paucity of systemic toxicity data for this chemical appears to be related to primary interest in testing for carcinogenicity. Treatment- related neoplasms developed in rats and mice that were treated with 1,2-diphenylhydrazine in a diet. An inconclusive chronic dermal carcinogenicity study of... 

Neurotoxicity. No clinical signs of central nervous system toxicity or histological alterations of nervous system organs and tissues were observed in rats or mice in the NCI (1978) chronic oral bioassay. Tests for neurotoxicity in animals may be appropriate if there is clinical evidence of neurological dysfunction in general oral or dermal toxicity studies of I 2-diphenylhydrazine. 

Systemic toxicity may occur after chronic or multiple exposures. Possible effects include gastrointestinal irritation with nausea, vomiting, and diarrhea, kidney injury such as oliguria or anuria, central nervous system depression, and vascular collapse. 

A low order of systemic toxicity was found in chronic feeding studies with rats. Administered in the diet for 2 years 0.215% sodium metabisulfite caused no adverse effects. Reproductive parameters were not affected in three-generation feeding smdies in rats at concentrations up to 13mmol/kg /day. ... 

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. 

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