Targets of toxicity

Penninks AH, Seinen W (1980) The lymphocyte as target of toxicity a biochemical approach to dialkyltin induced immunosuppression. Proceedings of the International Conference on the Immunological System as Target for Toxic Damage. Advances in Immunopharmacology, 2 41-60. 

Two studies on intermediate-duration exposure to mineral oil hydraulic fluids are available a single oral exposure rat study to MIL-H-5606 (Mattie et al. 1993), and an inhalation-exposure study in rats to Houghto-Safe 5047F (Kinkead et el. 1991). Because no other intermediate-duration studies were located, no inhalation or oral intermediate MRLs were derived. Inhalation, oral, and dermal systemic toxicity studies examining a number of end points would be useful in identifying the targets of toxicity of mineral oil hydraulic fluids. 

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. 

In contrast, in the pharmacological approach to toxicology, the potential targets of toxicity are first identified (Zbinden, 1986). Then criteria for relevant effects are established, usually based on experience with reference substances, and appropriate in vivo or in vitro experimental models are selected to assess the pertinent toxicological responses. 

Apply target-organ toxicity dose (TTD, see Section 10.5.1.1) modification of the HI method for overlapping targets of toxicity or access any unique critical effect with separate HQ. 

Animal studies also indicate that the respiratory system is a major target of toxicity following inhalation exposure to chlorine dioxide. Dalhamn (1957) reported the results of several inhalation studies in laboratory animals. In one study, a single 2-hour inhalation exposure of four rats to a chlorine dioxide concentration of 260 ppm (728 mg/m ) resulted in pulmonary edema and nasal bleeding. Respiratory distress was reported in three other rats subjected to 3 weekly 3-minute exposures to decreasing concentrations of airborne chlorine dioxide from 3,400 to 800 ppm (from 9,520 to 2,240 mg/m ) bronchopneumonia was observed in two of these rats. In a third rat study, repeated exposure to approximately 10 ppm (28 mg/m ) of chlorine dioxide (4 hours/day for 9 days in a 13-day period) resulted in rhinonhea, altered respiration, and respiratory infection. No indications of adverse effects were seen in rats exposed to approximately 0.1 ppm (0.28 mg/m ) of chlorine dioxide 5 hours /day for 10 weeks. 

Thyroid Effects. Limited information is available on thyroid effects in PBDE-exposed humans. There are suggestive occupational data as shown by effects that included increased serum FSH, low or borderline low serum T4, and increased thyroid antimicrosomal antibody titers in workers exposed to decaBDE and/or unspecified PBBs. There was no clear association between plasma levels of 2,2, 4,4-tetraBDE and thyroid hormone levels (free and total T3 and T4, TSH, free testosterone, follicle-stimulating hormone, lutenizing hormone, and prolactin) in men who consumed varying amounts of fatty fish from the Baltic Sea. Based on consistent evidence in animals, as summarized below, the thyroid is particularly sensitive to PBDEs and is a likely target of toxicity in exposed humans. 

Nervous System. The nervous system is also a common target of toxic metals particularly, organic metal compounds (see Chapter 16). For example, methylmercury, because it is lipid soluble, readily crosses the blood-brain barrier and enters the nervous system. By contrast, inorganic mercury compounds, which are more water soluble, are less likely to enter the nervous system and are primarily nephrotoxicants. Likewise organic lead compounds are mainly neurotoxicants, whereas the first site of inorganic lead is enzyme inhibition (e.g., enzymes involved in heme synthesis). 

Comparative Toxicokinetics. The animal data indicate that the nervous system is a sensitive target of toxicity for aluminum following oral exposure, as summarized in the Data Needs sections on Neurotoxicity. Although the interpretation of the human data is limited by poor exposure characterization, the occupational exposure studies suggest that neurotoxicity is also a sensitive end point following inhalation exposure (Hanninen et al. 1974 Hosovski et al. 1990 Rifat et al. 1990 Sim et al. 1997 Sjogren et al. 1996 White et al. 1992). The toxicokinetic properties of aluminum have been extensively studied in human and animals. The results of these studies suggest that the absorption, distribution, and excretion properties of aluminum are similar across species. 

White Phosphorus. Studies have shown that pregnant rats are more susceptible than nonpregnant female and male rats to the lethal effects of white phosphorus during late gestation or parturition. It is not known if pregnant women would also represent an unusually susceptible population. Human exposure to white phosphorus has shown that the liver, kidney, and cardiovascular systems are some of the primary targets of toxicity. Individuals with pre-existing liver, kidney, heart, or circulatory disorders may be unusually susceptible to white phosphorus toxicity. 

The targets of toxicity following dermal exposure cannot be identified because of the limited number of end points examined in the Ward (1928) study. No intermediate-duration dermal bum studies were identified. Inhalation, oral, and dermal (nonbum and bum) exposure studies would be useful to determine the primary targets of white phosphorus toxicity and dose-response relationships. There are populations surrounding hazardous waste sites that might be exposed to white phosphoms for similar durations. 

M usculoskeletal Effects. The musculoskeletal system does not appear to be a major target of toxicity in animals exposed to CDDs. Only one study reported hemorrhages in the musculoskeletal system of severely debilitated monkeys following dietary exposure to 0.011 g/kg/day of 2,3,7,8-TCDD for an intermediate duration (Allen et al. 1977). 

Pohl LR. An immunochemical approach to identifying and characterizing protein targets of toxic reactive metabolites. Chem Res Toxicol 1993 6 786-793. 

Rodier PM (1995) Developing brain as a target of toxicity. Environ Health Perspect, 103(Suppl 6) 73-76. 

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