Acute toxicity limitations

Evaluation of acute toxicity limits for purposes of risk analysis in the Czech Republic... 

Acute toxicity impact assessment involves the dose-effect relation, which is in the case of airborne toxicant the combination of exposure concentration and time. For the purpose of dose-effect relation characterization, acute toxicity limits are used. However, there are many different kinds of acute toxicity limits which differ in the impact on human health and/or in the time of exposure. The problem is, that the conditions under which each limit should be apphed are not specified. This situation can lead to significant problems in the application area of crisis management. 

There are several overviews of acute toxicity limits, among them two recent, giving principal insights to the problematic, which are the ACUTEX and the AEGL projects. The EU funded project ACUTEX (INERIS ef al. 2006) provides an acute toxicity limits overview, discuss the differences between the limits, deals with the practical application of the limits in the field of major accidents prevention and presents a completely new limit. The theoretical part is therefore devoted to this project. 

Comparison of acute toxicity limits was focused on threshold levels of individual acute toxicity limits. In toxicology, a threshold levels is considered to be a dose or endangering concentration of an agent imder which the effect is not observed or it is not e q)ected that the effect will occur. The most often applied acute... 

The difference between particular acute toxicity limits result, besides of the experiment differences, fi om threshold levels and time of the exposure. 

At the threshold level 3, the majority of acute toxicity limits is in agreement with above mentioned definition. Almost all the approaches (ERPG, AEGL, TEEL and LBW) specify threshold level to overcome life endangerment or death. There is a difference, however, when EEl refers to permanent inability and SEL refers only to prevention of death effects. 

The aim of this chapter is the discussion of acute toxicity limits used in the risk analysis in the context of major accident prevention in Czech Republic and pointing out related problems. 

Approximately 70% of evaluated companies store a dangerous substance classified as toxic or highly toxic. In approximately 25% of evaluated companies, the toxic substances are treated in such an amoimt and in such a physical form (gas, liquefied gas and highly volatile hquid) to be considered as possible threat for human health in the vicinity of the evaluated source of risk. Figure 2 shows the percentage occurrence of the use of individual software and methods in which acute toxicity limits are used. The versions of modeling software were not distinguished in the evaluation, because they were not always stated in risk analysis documents. The most often used software include TEREX (T-Soft 2000), SAVE II, ROZEX (TLP 2001), EFFECTS (TNO 2003), ALOHA (US ERA 2007) and CEI method (AIChE 1994). 

Figure 2. The percentage distribution ofthe most used modeling programs and method for acute toxicity limits in risk analysis condition in the CZ.

Environmentai NOEC (daphnia magna) >0.38 pg/l not found to be acutely toxic limit of aq. sol. may cause long-tenn adverse effects in aquatic environment avoid release to environment keep spills out of sewers and watercourses... 

Health, Safety, and Environmental Factors. Sulfur dioxide has only a moderate acute toxicity (183). The lowest pubHshed human lethal concentration is 1000 ppm for 10 months. The lowest pubHshed human toxic concentration by inhalation is 3 ppm for 5 days or 12 ppm for 1 hour. The lowest pubHshed human lethal concentration is 3000 ppm for 5 months. In solution (as sulfurous acid), the lowest pubHshed toxic dose is 500 flg/kg causing gastrointestinal disturbances. Considerable data is available by other modes of exposure and to other species NIOSH standards are a time-weighted average of 2 ppm and a short-term exposure limit of 5 ppm (183). 

Acute toxicity studies are often dominated by consideration of lethaUty, including calculation of the median lethal dose. By routes other than inhalation, this is expressed as the LD q with 95% confidence limits. For inhalation experiments, it is convenient to calculate the atmospheric concentration of test material producing a 50% mortaUty over a specified period of time, usually 4 h ie, the 4-h LC q. It is desirable to know the nature, time to onset, dose—related severity, and reversibiUty of sublethal toxic effects. 

In order to expedite the launch of a new chemical and allow further time to complete the toxicological package for full registration, a "limited announcement" is normally used. This requkes only parts of the full toxicological packages, usually acute toxicity and Ames test. Consequentiy, it is less expensive ( 20,000) and quicker (90 days) than full registration. However, only 1 t or less of the chemical per year is allowed to be sold in the EEC. 

Many very hazardous solvents, such as benzene and carbon tetrachloride, were widely used until the 1970s. The situation was very similar for the use of pesticides. Among the toxic pesticides that were still in wide use 20 years ago were chlorophenols, DDT, lindane, and arsenic salts, all of which are classified as human carcinogens as well as being acutely toxic. Fortunately, use of these kinds of very toxic chemicals is now limited in the industrialized world. However, because the number of chemicals used in various industries continues to increase, the risks of long-term health hazards due to long-term exposure to low concentrations of chemicals continues to be a problem in the workplace. 

Except for polybrominated biphenyls (PBB), a limited number of studies regarding the toxicity of aromatic brominated compounds has been performed. Some experiments suggest a moderate acute toxicity of these compounds (ref. 1). 

The results of metabolism studies with laboratory animals and livestock indicate that endosulfan does not bioconcentrate in fatty tissues and milk. Lactating sheep administered radiolabeled endosulfan produced milk containing less than 2% of the label. Endosulfan sulfate was the major metabolite in milk (Gorbach et al. 1968). A half-life of about 4 days was reported for endosulfan metabolites in milk from survivors of a dairy herd accidentally exposed to acutely toxic concentrations of endosulfan endosulfan sulfate accounted for the bulk of the residues detected in the milk (Braun and Lobb 1976). No endosulfan residues were detected in the fatty tissue of beef cattle grazed on endosulfan-treated pastures for 31-36 days (detection limits of 10 ppm for endosulfan, 40 ppm for endosulfan diol) the animals began grazing 7 days after treatment of the pastures. Some residues were detected in the fatty tissue of one animal administered 1.1 mg/kg/day of endosulfan in the diet for 60 days. No endosulfan residues were... 

Mineral Oil Hydraulic Fluids. There is limited information on the acute toxicity of mineral oil hydraulic fluids to humans. A single case report of a child accidentally ingesting automotive transmission fluid reported respiratory and gastrointestinal effects (Perrot and Palmer 1992). 

Waste characteristics, which may limit the effectiveness or feasibility of the remedial technologies quantity/concentration, chemical composition, acute toxicity, persistence, biodegradability, radioactivity, ignitability, reactivity/corrosivity, infectiousness, solubility, volatility, density, partition coefficient, compatibility with chemicals, and treatability... 

Phase I The preliminary studies in humans are designed to evaluate the pharmacokinetics and the acute toxicity/tolerability of the potential dmg. Usually, phase I studies are carried out in a very small population [15—40] of healthy male volunteers. Thus, the nature of the population tested and the small number of individuals involved limits the scope of pharmacogenomics to the study of genetic variability in drug metabolism. 

There are no structure-activity relationships applicable to estimating acute exposure limits for arsine. The nature and rapidity of its toxicity are notably different from other inorganic arsenic compounds. 

Intraspecies Because the species used was the most sensitive to monomethylhydrazine toxicity and the most closely related to humans, an uncertainty factor of 3 is justified. A factor of 3 was used. Although the mechanism of toxicity is uncertain and sensitivity among individuals may vary, the exposure-response relationship is steep, suggesting limited variability in the toxic response to methylhydrazine. Furthermore, it is likely that acute toxic responses are, at least initially, a function of the extreme reactivity of methylhydrazine. The interaction of the highly reactive monomethylhydrazine with tissues (e.g., pulmonary epithelium) is not likely to greatly vary among individuals. 

In addition to the chemicals included on the other lists, the CDC also included heavy metals such as arsenic, lead, and mercury volatile solvents such as benzene, chloroform, and bromoform decomposition products such as dioxins and furans polychlorinated biphenyls (PCBs) flammable industrial gases and liquids such as gasoline and propane explosives and oxidizers and all persistent and nonpersistent pesticides. Agents included in this volume are limited to those that are most likely to pose an acute toxicity hazard. 

Data on the bioavailability of PCDDs are limited. It is known that PCDDs incorporated into wood as a result of chlorophenol (preservative) treatment are bioavailable. Swine and poultry using chlorophenol-treated wooden pens or litter have been found to be contaminated with PCDDs (NRCC 1981). Toxicities of individual PCDD isomers can vary by a factor of 1000 to 10,000 for isomers as closely related as 2,3,7,8-TCDD and 1,2,3,8-TCDD, or 1,2,3,7,8-penta-CDD and 1,2,4,7,8-penta-CDD (Rappe 1984). Isomers with the highest biological activity and acute toxicity have four to six chlorine atoms, and all lateral (i.e., 2,3,7, and 8) positions substituted with chlorine. On this basis, the most toxic PCDD isomers are 2,3,7,8-TCDD, 1,2,3,7,8-penta-CDD, 1,2,3,6,7,8-hexa-CDD, 1,2,3,7,8,9-hexa-CDD, and 1,2,3,4,7,8-hexa-CDD (Rappe 1984). Ishizuka et al. (1998) have assigned toxic equivalencies for various PCDDs, with 2,3,7,8-TCDD given a value of 1 (highest biological activity), followed by a value of 0.5 for 1,2,3,7,8-penta-CDD a value of 0.1 for three PCDD isomers (1,2,3,4,7,8-hexa-CDD, 1,2,3,4,7,8-hexa-CDD, 1,2,3,7,8,9-hexa-CDD), a value of 0.01 for 1,2,3,4,6,7,8-hepta-CDD and a value of 0.001 for 1,2,3,4,6,7,8,9-octa-CDD. 

---