Quantifying the benefits of using read-across and in silico techniques to fulfill hazard data requirements for chemical categories.

Substantial benefits are realized through the use of read-across and in silico techniques to fill data gaps for structurally similar substances. Considerable experience in applying these techniques was gained under two voluntary high production volume (HPV) chemical programs - the International Council of Chemical Associations' (ICCA) Cooperative Chemicals Assessment Programme (with the cooperation of the Organization of Economic Cooperation and Development) and the U.S. Environmental Protection Agency's HPV Challenge Program. These programs led to the compilation and public availability of baseline sets of health and environmental effects data for thousands of chemicals. The American Cleaning Institute's (ACI) contribution to these national and global efforts included the compilation of these datasets for 261 substances. Chemicals that have structural similarities are likely to have similar environmental fate, physical-chemical and toxicological properties, which was confirmed by examining available data from across the range of substances within categories of structurally similar HPV chemicals. These similarities allowed the utilization of read-across, trend analysis techniques and qualitative structure activity relationship ((Q)SAR) tools to fill data gaps. This paper presents the first quantification of actual benefits resulting from avoided testing through the use of read-across and in silico tools. Specifically, in the evaluation of these 261 noted substances, the use of 100,000-150,000 test animals and the expenditures of $50,000,000 to $70,000,000 (US) were avoided.

Managing the Risk of Occupational Allergy in the Enzyme Detergent Industry.

Enzyme proteins have potential to cause occupational allergy/asthma. Consequently, as users of enzymes in formulated products, detergents manufacturers have implemented a number of control measures to ensure that the hazard does not translate into health effects in the workforce. To that end, trade associations have developed best practice guidelines which emphasize occupational hygiene and medical monitoring as part of an effective risk management strategy. The need for businesses to recognize the utility of this guidance is reinforced by reports where factories which have failed to follow good industrial hygiene practices have given rise to incidences of occupational allergy. In this article, an overview is provided of how the industry guidelines are actually implemented in practice and what experience is to be derived therefrom. Both medical surveillance and air monitoring practices associated with the implementation of industry guidelines at approximately 100 manufacturing facilities are examined. The data show that by using the approaches described for the limitation of exposure, for the provision of good occupational hygiene and for the active monitoring of health, the respiratory allergenic risk associated with enzyme proteins can be successfully managed. This therefore represents an approach that could be recommended to other industries contemplating working with enzymes.

Comparative assessment of the acute skin irritation potential of detergent formulations using a novel human 4-h patch test method.

Predictive skin irritation test methods, which do not require use of animals, are needed for the pre-market assessment of detergent formulations. The utility of a novel and ethical human acute skin irritation patch test method, originally developed for chemical skin irritation assessment, was evaluated. In this IRB-approved method, subjects were patched under occlusion for increasing periods of time up to 4h in duration. The total incidence of positive skin reactions for test products was compared to a positive control (20% aqueous sodium dodecyl sulfate [SDS]). Acutely irritating formulas were defined as those showing a significantly increased or equal incidence of positive responders compared with that of SDS. The time of exposure required for 50% of subjects to show a positive skin reaction (TR50 value) was calculated for each product and enabled test product comparisons within and between studies. Using this approach, 24 detergent formulations of various types were tested in seven individual studies. The skin irritation profiles were generally consistent within product types, which could be categorized as follows (by decreasing irritancy): mold/mildew removers (average TR50 = 0.37 h) > disinfectants/sanitizers (0.64 h) > fabric softener concentrate (1.09 h) = aluminum wash (1.20 h) > 20% SDS (1.81 h) > liquid laundry detergents (3.48 h) > liquid dish detergents (4.16 h) = liquid fabric softeners (4.56 h) = liquid hand soaps (4.58 h) = shampoos (5.40 h) = hard surface cleaners (6.34 h) > powder automatic dish detergents (>16 h) = powder laundry detergents (>16 h). In addition to formulation effects, some seasonal effects were noted; particularly greater winter-time reactivity to 20% SDS and the hard surface cleaner and liquid laundry formulations. These results demonstrate the utility of this patch test method for the comparative skin irritation assessment of these different product types.

Quantitative microbial risk assessment of antibacterial hand hygiene products on risk of shigellosis.

There are conflicting reports on whether antibacterial hand hygiene products are more effective than nonantibacterial products in reducing bacteria on hands and preventing disease. This research used new laboratory data, together with simulation techniques, to compare the ability of nonantibacterial and antibacterial products to reduce shigellosis risk. One hundred sixtythree subjects were used to compare five different hand treatments: two nonantibacterial products and three antibacterial products, i.e., 0.46% triclosan, 4% chlorhexidine gluconate, or 62% ethyl alcohol. Hands were inoculated with 5.5 to 6 log CFU Shigella; the simulated food handlers then washed their hands with one of the five products before handling melon balls. Each simulation scenario represented an event in which 100 people would be exposed to Shigella from melon balls that had been handled by food workers with Shigella on their hands. Analysis of experimental data showed that the two nonantibacterial treatments produced about a 2-log reduction on hands. The three antibacterial treatments showed log reductions greater than 3 but less than 4 on hands. All three antibacterial treatments resulted in statistically significantly lower concentration on the melon balls relative to the nonantibacterial treatments. A simulation that assumed 1 million Shigella bacteria on the hands and the use of a nonantibacterial treatment predicted that 50 to 60 cases of shigellosis would result (of 100 exposed). Each of the antibacterial treatments was predicted to result in an appreciable number of simulations for which the number of illness cases would be 0, with the most common number of illness cases being 5 (of 100 exposed). These effects maintained statistical significance from 10(6) Shigella per hand down to as low as 100 Shigella per hand, with some evidence to support lower levels. This quantitative microbial risk assessment shows that antibacterial hand treatments can significantly reduce Shigella risk.

Relevance of sensitization to occupational allergy and asthma in the detergent industry.

There exists considerable historic experience of the relationship between exposure and both the induction of sensitization and the elicitation of respiratory symptoms from industrial enzymes of bacterial and fungal origin used in a wide variety of detergent products. The detergent industry in particular has substantial experience of how the control of exposure leads to limitation of sensitization with low risk of symptoms. However, the experience also shows that there are substantial gaps in knowledge, even when the potential occupational allergy problem is firmly under control, and also that the relationship between exposure and sensitization can be hard to establish. The latter aspect includes a poor appreciation of how peak exposures and low levels of exposure over time contribute to sensitization. Furthermore, while a minority of workers develop specific IgE, essentially none appear to have symptoms, a situation which appears to contradict the allergy dogma that, once sensitized, an individual will react to much lower levels of exposure. For enzymes, the expression of symptoms occurs at similar or higher levels than those that cause induction. In spite of some knowledge gaps, medical surveillance programs and constant air monitoring provide the tools for successful management of enzymes in the occupational setting. Ultimately, the knowledge gained from the occupational setting facilitates the completion of safety assessments for consumer exposure to detergent enzymes. Such assessments have been proven to be correct by the decades of safe use both occupationally and in consumer products.

The toxicology and immunology of detergent enzymes.

Detergent enzymes have a very good safety profile, with almost no capacity to generate adverse acute or chronic responses in humans. The exceptions are the limited ability of some proteases to produce irritating effects at high concentrations, and the intrinsic potential of these bacterial and fungal proteins to act as respiratory sensitizers, demonstrated in humans during the early phase of the industrial use of enzymes during the 1960s and 1970s. How enzymes generate these responses are beginning to become a little clearer, with a developing appreciation of the cell surface mechanism(s) by which the enzymatic activity promotes the T-helper (T(H))-2 cell responses, leading to the generation of IgE. It is a reasonable assumption that the majority of enzyme proteins possess this intrinsic hazard. However, toxicological methods for characterizing further the respiratory sensitization hazard of individual enzymes remains a problematic area, with the consequence that the information feeding into risk assessment/management, although sufficient, is limited. Most of this information was in the past generated in animal models and in vitro immunoassays that assess immunological cross-reactivity. Ultimately, by understanding more fully the mechanisms which drive the IgE response to enzymes, it will be possible to develop better methods for hazard characterization and consequently for risk assessment and management.

Proposed new classification scheme for chemical injury to the human eye.

PURPOSE: Various ocular alkali burn classification schemes have been published and used to grade human chemical eye injuries for the purpose of identifying treatments and forecasting outcomes. The ILSI chemical eye injury classification scheme was developed for the additional purpose of collecting detailed human eye injury data to provide information on the mechanisms associated with chemical eye injuries. This information will have clinical application, as well as use in the development and validation of new methods to assess ocular toxicity. METHODS: A panel of ophthalmic researchers proposed the new classification scheme based upon current knowledge of the mechanisms of eye injury, and their collective clinical and research experience. Additional ophthalmologists and researchers were surveyed to critique the scheme. The draft scheme was revised, and the proposed scheme represents the best consensus from at least 23 physicians and scientists. RESULTS: The new scheme classifies chemical eye injury into five categories based on clinical signs, symptoms, and expected outcomes. Diagnostic classification is based primarily on two clinical endpoints: (1) the extent (area) of injury at the limbus, and (2) the degree of injury (area and depth) to the cornea. CONCLUSIONS: The new classification scheme provides a uniform system for scoring eye injury across chemical classes, and provides enough detail for the clinician to collect data that will be relevant to identifying the mechanisms of ocular injury.