Human limitations

A. Probably carcinogenic ro humans Limited evidence on carcinogenicity in humans and sufficient evidence on carcinogenicity in experimental animals and other relevant evidence... 

The first component of the systems approach to error reduction is the optimization of human performance by designing the system to support human strengths and minimize the effects of human limitations. The hiunan factors engineering and ergonomics (HFE/E) approach described in Section 2.7 of Chapter 2 indicates some of the techniques available. Design data from the human factors literature for areas such as equipment, procedures, and the human-machine interface are available to support the designer in the optimization process. In addition the analytical techniques described in Chapter 4 (e.g., task analysis) can be used in the development of the design. 

No studies were located regarding toxicokinetic data in humans. Limited information is available regarding the toxicokinetic differences among animal species. Rats, mice, mink, and dogs showed rapid absorption, wide distribution, and over 90% urinary excretion of diisopropyl methylphosphonate or its metabolites. However, the rates of absorption and patterns of distribution varied (Hart 1976 Weiss et al. 1994). The mechanism of toxicity is also undetermined. From the limited data available, it is not possible to determine the degree of correlation between humans and animals. 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

Vermeire et al. (2001) concluded that currently no adequate proposal for a database-derived distribution of the intraspecies factor can be made. Therefore, a distribution consistent with the default value of 10 as proposed by Slob and Pieters (1998) based on a theoretical distribution will be used for derivation of Human Limit Values. For workers, a distribution consistent with the default value for workers of 3, considered to be conservative, was proposed in parallel with the approach of Slob and Pieters (1998). 

Hepatic Effects. No information is available on the hepatic effects of HDI in humans. Limited information exists on these effects in laboratory animals and is confined to inhalation studies. One study of intermediate-duration showed decreased liver weights in female rats dosed at 0.3 ppm (Mobay Corporation 1984) however, 2 studies of longer durations and slightly lower inhaled doses showed no ehanges in liver weights attributable to HDI toxieity (Mobay Corporation 1988, 1989). It appears that the ehanges in liver weights are a transitory phenomenon in laboratory animals. 

In the effects assessment step the relationship between the level of exposure and the incidence, nature, and severity of an (adverse) effect following the exposure is determined. For most types of effects, it is assumed that there is a minimum dose or concentration below which adverse effects will not occur the no effect level or threshold. To determine the threshold, different doses are tested, for most chemical hazards usually in laboratory animals. In toxicology, the highest tested dose without adverse effects is called the no observed adverse effect level (NOAEL). Based on the NOAEL established in an experimental study, a human limit value can be calculated, taking into account uncertainties and differences in experimental design and circumstances. Uncertainties and differences are accounted for by uncertainty factors (e.g., for interspecies differences, intraspecies variability, and exposure duration). For some types of substances, it is assumed that every level of exposure can result in adverse effects, in which case no threshold would exist. This, for instance, is assumed to apply for genotoxic carcinogens. 

Besides, the director wants to be a great artist. Great artists are supposed to point out human foibles and the tragedies brought on by human limitations. Isn t that what Shakespeare did They don t pander to the sensibilities of the unwashed masses. So the director closes his eyes and sets to work imagining some different scenarios. 

Intermediate-Duration Exposure. No reliable information is available on the effects of repeated-dose exposure in humans. Limited information is available on the effects of repeated inhalation and oral exposures to 1,1-dichloroethane in animals. The studies reviewed indicate that 1,1-dichloroethane is possibly nephrotoxic, but this effect has only been demonstrated at high doses in one of several species tested. No other toxic effects have been attributed to 1,1-dichloroethane following repeated-dose exposures in animals. An intermediate MRL could not be derived for any routes of exposure. More information on the systemic effects of repeated-dose exposures in animals, particularly by the inhalation route since this is the most likely route of human exposure, would be useful to determine whether nephrotoxic effects observed in one study are an actual result of exposure to 1,1-dichloroethane, to determine if 1,1-dichloroethane reacts like other chlorinated aliphatics (e.g., causes neuro-and liver toxicity), and to more fully assess potential human health hazards from repeated exposure to 1,1-dichloroethane. This latter justification is particularly important since repeated exposure to low levels of 1,1-dichloroethane may be of more concern than short-term exposure to very high levels based on the current use and/or disposal of this chemical. 

CONSENSUS REPORTS NTP 10th Report on Carcinogens. lARC Cancer Review Group 2A IMEMDT 7,310,87 Animal Inadequate Evidence IMEMDT 13,141,77 Human Limited Evidence IMEMDT 13,141,77 IMEMDT 24,135,80 Animal Limited Evidence IMEMDT 24,135,80 IMEMDT 24,135,80. Reported in EPA TSCA Inventory. 

CONSENSUS REPORTS lARC Cancer Review Group 2B IMEMDT 7,56,87 Human Limited Evidence IMEMDT... 

CONSENSUS REPORTS lARC Cancer Review Group 1 IMEMDT 7,100,87 Human Limited Evidence IMEMDT 2,48,73 Human Sufficient Evidence IMEMDT 23,39,80 Animal Inadequate Evidence IMEMDT 2,48,73 IMEMDT 23,39,80. Reported in EPA TSCA Inventory. Arsenic and its compounds are on the Community Right-To-Know List. EPA Extremely Haxardous Substances List. OSHA PEL TWA 0.01 mg(As)/m3 Cancer Hazard... 

CONSENSUS REPORTS NTP 10th Report on Carcinogens. I ARC Cancer Review Group 2A IMEMDT 7,150,87 Human Limited Evidence IMEMDT 26,79,81 Animal Sufficient Evidence IMEMDT 26,79,81. NCI Carcinogenesis Studies (ipr) Some Evidence rat CANCAR 40,1935,77 Clear Evidence mouse CANCAR 40,1935,77. EPA Genetic Toxicology Program. 

CONSENSUS REPORTS lARC Cancer Review Animal Inadequate Evidence IMEMDT 21,139,79 Human Limited Evidence IMEMDT 21,139,79. 

---