Integrated systems risk factors

Three levels of risk are suggested here (low, medium, and high) although some pharmaceutical and healthcare companies may like to consider five levels of risk to match the system integrity levels defined by lEC/ISO 61508 for safety critical systems. Each system should be rated against a number of weighted risk factors to determine an overall level of risk. Seven example risk factors are considered in Table 14.4 ... 

Airway administration of liposome complexes was used for the treatment of pulmonary diseases including cystic fibrosis. Cationic liposome/DNA complex showed no adverse effect towards airway epithelial integrity (190) therefore, the cationic lipid-based delivery system proved to be appropriate for use in human trials for cystic fibrosis (CF). A series of pre-clinical trials were done in CF patients with intranasal instillation to evaluate the risk factors associated with the treatment (191-193). Because there was no apparent toxicity associated with lipoplexes as was seen from these trials, progress had been made in delivering the complexes to the entire lung by aerosol in CF patients (192,194,195). By nebulization, the DNA-liposome complex was delivered into the airways of mutant mice to obtain human cystic fibrosis transmem-... 

The preliminary risk assessment is made by a risk graph qualitative method described in lEC 61508-5 Annex E according Figure E.l (Figure 3) and Table E.l. This method has been used extensively within the machinery sector, see ISO 14121-2 and Annex A of ISO 13849-1, and enables the safety integrity level to be determined from knowledge of risk factors associated with the hoist machinery and it control system. 

Integrated Risk Infonnation System (IRIS) A USEPA data base containing verified RfDs and slope factors and up-to-date health risk and EPA regulatory information for numerous chemicals. IRIS is the USEPA s preferred source for toxicity information for Superfund studics/projects. 

No inhalation slope factor is available for aniline, and the available inhalation studies did not examine the endpoint of carcinogenicity. Based on the chronic oral administration of aniline hydrochloride to CD-F rats (CUT 1982), U.S. EPA in its Integrated Risk Information Systems (IRIS) has estimated an oral slope factor of 5.7x1 OP Vrng/kg/d (U.S. EPA 1994). In that study, spleen tumor incidences in rats administered 0, 200, 600, or 2,000 ppm in the diet were 0/64, 0/90, 1/90, and 31/90, respectively. Aniline also has genotoxic action. 

Neither an inhalation nor an oral slope factor is currently available for monomethylhydrazine. Slope factors for 1,1-dimethylhydrazine and 1,2-dimethylhydrazine were available but have been withdrawn from the U.S. EPA Integrated Risk Information System (IRIS) (U.S. EPA 1986). For a preliminary carcinogenicity assessment, the withdrawn inhalation slope factor for 1,1-dimethylhydrazine (cited in ATSDR 1994) will be used as a surrogate for monomethylhydrazine. The assessment follows previously described methodologies (NRC 1985 Henderson 1992). 

Floating vessels for offshore operations offer reduced installation costs but also present additional vulnerability factors. All floating structures must ensure buoyancy integrity is maintained otherwise the vessel may sink with catastrophic results. Similarly propulsion are provided at some installations to provided position stability. All major vessels are required by insurance requirements and most marine regulations to maintain buoyancy systems and loss of position stability will impact ongoing operations. Both of these systems can therefore be considered critical support systems and must be evaluated for risk and loss control measures either thorough duplication and protection measures or a combination of both. 

The EPA controls the regulation of poisonous substances in the drinking water and in food, and provides an Integrated Risk Information System (IRIS) database for assessment in their Exposure Factors Handbook. They published drinking water standards in 1994 in terms of MCE in mg/L and as a health advisory RfD in mg/(kg day) of intake (Chapter 6). Some typical values are given in table 10.3, which shows a tremendous range of five orders of magnitude between the mildly toxic xylene and the extremely toxic white phosphoms. 

Sexual function and fertility reflect a wide variety of functions that are necessary for reproduction and may be affected by exposure to environmental factors. Any disturbance in the integrity of the reproductive system may affect these functions. Patterns of reported infertility vary around the world, but approximately 10% of all couples experience infertility at some time during their reproductive years. Human studies on altered sexual function/fertility provide the most direct means of assessing risk, but data are often unavailable. For many environmental chemicals, it is still necessary to rely on information derived from experimental animal models and laboratory studies. 

It is noteworthy that the styrene reference concentration (RfC) in the Integrated Risk Information System is based on the biomarker-response relationship found in workers (Mutti et al. 1984 EPA 1998). The Environmental Protection Agency (EPA) used the relationship of urinary biomarker to ambient-air concentration of workers to develop an RfC that was adjusted for the difference in exposure time between the workplace and the general population. That is a valid approach because it derives a workplace concentration-toxicity relationship in workers, which can then be adjusted for the general population to account for differences in exposure time and can take uncertainty factors into account. It is different from direct adjustment of the styrene BEI to evaluate human population biomonitoring data on styrene metabolites in urine, which would have the uncertainties described above and in Chapter 5. 

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