Safety margin, comparison with

Identification of risk levels and margins of safety in comparisons with other commonly encountered chemicals do not finally solve the problem whether a particular chemical risk constitutes a socially acceptable risk. This must finally be determined in the social institutions mentioned earlier at the various political jurisdictions. Whether a risk will be socially acceptable depends not only on the level of risk, which we have dealt with here, but on the nature of the risk, on who assumes the risk, who receives the benefit, and one s personal philosophy of accepting any risk versus zero risk. 

Bacterial spores are the most resistant of all microbial forms to chemical treatment. The majority of antimicrobial agents have no useful sporicidal action, with the exception of the aldehydes, halogens and peroxygen compounds. Such chemicals are sometimes used as an alternative to physical methods for sterilization ofheat sensitive equipment. In these circumstances, correct usage of the agent is of paramount importance since safety margins are lower in comparison with physical methods of sterilization (Chapter 20). 

This exposure relationship is frequently more important in establishing human safety margins, as dose alone may be subject to a variety of differences between species such as absolute bioavailability, distribution, and excretion. This aspect, now commonly referred to as "toxicokinetics," has been outlined in an ICH guideline.6 This guideline specifies minimum requirements in terms of number of time points examined, number of animals per time point, and the requirements for calculation of various pharmacokinetic parameters such as Cmax, AUC. These will become important for comparison with human data as it becomes available later. 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

Acute toxicity studies have been performed in various animals mice, rats, rabbits, cats, dogs, and macaques.18,20,35,36,40,44 Lethal doses of DMHP are extremely high, in comparison with the small doses required to produce its pharmacodynamic effects. For instance, the intravenous LD50 in mice is 63 mg/kg, whereas the minimal effective dose in 50% of the animals (MED50) is 0.075 mg/kg, for a safety factor of 840. The dose required to produce tranquilization in the unanesthetized dog is 0.05 mg/kg, and the minimal lethal dose is 10 mg/kg by the same route. The margin of safety in the dog is about 200. By comparison, the margin of safety of reserplne is 5.0. 

The 1996 Food Quality Protection Act (FQPA) now requires that an additional safety factor of 10 be used in the risk assessment of pesticides to ensure the safety of infants and children, unless the EPA can show that an adequate margin of safety is assured with out it (Scheuplein, 2000). The rational behind this additional safety factor is that infants and children have different dietary consumption patterns than adults and infants, and children are more susceptible to toxicants than adults. We do know from pharmacokinetics studies with various human pharmaceuticals that drug elimination is slower in infants up to 6 months of age than in adults, and therefore the potential exists for greater tissue concentrations and vulnerability for neonatal and postnatal effects. Based on these observations, the US EPA supports a default safety factor greater or less than 10, which may be used on the basis of reliable data. However, there are few scientific data from humans or animals that permit comparisons of sensitivities of children and adults, but there are some examples, such as lead, where children are the more sensitive population. It some cases qualitative differences in age-related susceptibility are small beyond 6 months of age, and quantitative differences in toxicity between children and adults can sometimes be less than a factor of 2 or 3. 

As may be discerned from earlier discussion, in comparison with preparation in the laboratory, the industrial manufacture of azides requires processes which are not only suitable for quantity production, but which confer superior handling characteristics to the bulk and to the milligram quantities into which the bulk is subdivided. The processes must assure a reliability of performance and margins of safety which the laboratory researcher does not require. At the same time the quantity production must be achieved within acceptable bounds of economy (in both time and money), yet with a degree of control normally obtainable only in a laboratory. 

Compliance with the design rules of ASME Code Section VIII of 1949 and subsequent verification of the stress analysis and comparison with the current ASME Section III Class 1 design allowable stresses ensure that the tank stresses are within allowable limits and provide adequate safety margins. In another stress evaluation performed by Quadrex Corporation, ASME Section VIII, Division 2 rules and allowable stresses were used, and the stresses in the tank and the expansion ring were found to satisfy the applicable criteria. 

The results of safety analyses of the Super LWR are summarized in Fig. 1.48 [56]. The temperature rises of the fuel cladding of Super LWR are illustrated in comparison with the criteria and margins in Fig. 1.49. Safety characteristics of the Super LWR are summarized in Table 1.13. 

The direct comparison of a POD (DNEL) with the estimated exposure (E) leads to the establishment of a ratio (DNEL/E), often denoted as the margin of safety (MOS) or margin of exposure (MOE). 

Guidance to date supports the risk assessment principles for general chemical substances already published by the Commission (1996). Consequently, the risk characterisation simply involves a quantitative comparison of the outcome of the hazard/effects assessment with the exposure assessment. For human risk this involves the calculation of the TER (Toxicity Exposure Ratio) and comparing it with the MOS (Margin Of Safety). For environmental risk the PEC/PNEC ratio (Predicted Environmental Concentration versus the Predicted No-Effect Concentration) for the various environmental compartments. 

These are conducted to gain information on the cumulative irritancy of a product. This type of test is designed to mirror the intended use of the product, but exposure may also be exaggerated, to provide a greater margin of safety in the risk assessment on the product and also to provide information on problems that may be encountered should the product be misused. Some methods are designed to simulate the normal use of products, with controlled exposure. The skin irritation is monitored and comparisons made between the test and control product in the same panellist. The controls are... 

Comparison of RfD with Human Toxicity Data. The RfDe is compared to the available human toxicity data in Table 27. One study in humans indicated that an oral dose of 2.3 Xg kg d for 3 d resulted in 27% and 33% RBC-AChE inhibition but no toxic effects. This dose is about 115 times greater than the derived RfDe. For an adverse-effect level (i.e., mild toxic effect at 29 (Ag kg d ) (Grob and Harvey 1958), the margin of safety would be about 10 times greater than that for 27%-33% RBC-AChE inhibition. 

DRM Method The results of the previous steps provide point estimates and credibility intervals for the probabilities of safety events in various conditions. Comparison of these results with safety criteria provides insight in risk acceptability and risk margins. Furthermore, these results can be used to identify safety bottlenecks (aspects of the operation that contribute to unacceptable risk levels) and they provide a basis to determine safety requirements and safety objectives. 

---