Safety Factor Approach Research Articles

Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling

A physiologically based pharmacokinetic (PB-PK) model for CHCl 3 has been used to prepare estimates of the probability that human populations exposed to low levels of CHCl 3 will develop liver tumors similar to those seen in rodent bioassays. The PB-PK model for CHCl 3 was based on a model reported earlier by Corley et al. (1990), but this model differed from that of Corley et al. in that it was also capable of describing a pharmacodynamic endpoint: induction of cytotoxicity in the liver of CHCl 3-exposed animals produced by reactive metabolites of CHCl 3. Pharmacodynamic descriptions in this model were derived from experimental measurements of cell replication ([ 3H]thymidine incorporation) as well as from quantitative histopathology in the liver of rats and mice. Two different approaches were used for hazard evaluation: (1) a “Safety Factor” approach based on no observed effect levels for liver tumors, and (2) calculation of lower confidence limits on risk-specific doses with the GLOBAL83 computer program. In each case, cytotoxicity produced by reactive CHCl 3 metabolites was used as the measure of “dose” to the liver. The Safety Factor approach suggested that continuous exposure of human populations to concentrations of CHCl 3 less than 2840 ppb in air or 13,900 ppb in water would not be likely to significantly increase the risk of developing liver tumors. The second approach suggested a “plausible upper 95% confidence limit” of 1 × 10 −5 for lifetime excess cancer risk for human populations continuously exposed to 2200 or 13,100 ppb CHCl 3 in air or water, respectively.

Uncertainties in the risk assessment of three mycotoxins: aflatoxin, ochratoxin, and zearalenone

The risk assessment of mycotoxins is made up of two major components: an exposure assessment and a hazard assessment. There are many uncertainties in both of these components. This paper will briefly discuss the various aspects of the risk assessment process as it applies to mycotoxins and will then focus mainly on some of the uncertainties in the hazard assessment component of several carcinogenic mycotoxins. To arrive at an estimated "safe dose" (end point of the hazard assessment), we have previously used two major approaches: the no observed effect level (NOEL) divided by a safety factor approach and a mathematical (robust linear) extrapolation to a "virtual safe dose." Both of these approaches use only points from the no observed effect region of the dose-response curve and ignore valuable data from the response region. It is proposed to use the dose at which 50% of the animals would have developed tumors (the TD50) divided by a large safety factor of 50,000 as an additional estimate of "safe dose". For many studies, the TD50 lies within the observed response region of the dose-response curve and may have more validity. It is also suggested in certain cases that some of the uncertainties regarding the NOEL can be reduced if one uses a statistically derived no effect level (NEL).

Structures that Fail Benignly

SUMMARY The safety factor, load factor and fail-safe approaches to designing for strength are briefly reviewed. It is shown that the first two are essentially the same when considering the general fitness-for-purpose philosophy. Fail-safe is advantageous when dealing with modern materials, such as structural ceramics, and with fatigue, when statistical considerations become important. An extension of the fail-safe approach, entitled ‘benign failure’ is finally presented.

Assessment of the developmental risks resulting from occupational exposure to select glycol ethers within the semiconductor industry.

This risk assessment evaluates the potential human hazards of adverse developmental effects posed by exposure to 2-ethoxyethanol (2-EE), 2-ethoxyethanol acetate (2-EEA), 2-methoxyethanol (2-ME), and 2-methoxyethanol acetate (2-MEA) as they are currently used in semiconductor manufacturing. These glycol ethers are contained in positive photoresists used in the wafer fabrication process. The available data on the developmental toxicology of these glycol ethers indicates that each can selectively affect the offspring of pregnant animals that have been exposed to relatively low vapor concentrations. For these chemicals, the ratio of the lowest dose which adversely affected the pregnant animals (A) and the lowest dose which produced developmental effects in offspring (D), e.g., A/D ranged from 1-5. Approximately 400 workplace air samples of 4-8 h duration, both personal and area, from seven different companies were used to assess the degree of inhalation exposure during the manufacture of wafers. The geometric mean results obtained during personal sampling of workplace air for 2-EE, 2-EEA, 2-ME, and 2-MEA were 0.36, 0.02, 0.10, and 0.01 ppm, respectively. These levels are 14- to 500-fold lower than the applicable threshold limit value (TLV) currently recommended by the American Conference of Governmental Industrial Hygienists (ACGIH). Specifically, the margins of safety between the typical occupational exposure and the TLV for 2-ME, 2-EE, 2-MEA, and 2-EEA are 50, 14, 500, and 250, respectively. The TLVs for these chemicals were set at levels considered sufficiently low to protect workers and their offspring from adverse effects and are about 2- to 10-fold lower than the various no-observed-effect levels (NOELs) obtained in animal tests. Based on more recent data, lower TLVs are indicated. The safety-factor approach, rather than mathematical models developed for estimating cancer risks, was used in this analysis. Historical data have shown that the application of safety factors of 10-100 to the NOEL, as determined in Segment II developmental toxicology tests in animals, should be adequate to protect humans. In its risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) selected the uncertainty-factor approach as the most reasonable one for evaluating the hazards of developmental toxicants. This assessment indicates that the airborne concentrations of these glycol ethers in the semiconductor industry are, in general, sufficiently low to protect employees against their adverse developmental and reproductive effects as well as any other toxic effects as long as dermal exposure is minimal.

Chance Constrained Model for River Water Quality Management

A chance constrained model is proposed, in which the main stream, tributaries, and storm water are considered as random variables to determine the most economical level of wastewater treatment at each discharge city or industry along a river basin. The model considers the risk of violation of the stream‐water quality explicitly and therefore, provides a more rational approach than the traditional design value or safety factor approach, e.g., the lowest 7‐day moving average of daily flow rate over a 10‐yr period. The model is shown to be equivalent to a linearly constrained program, thus enabling the application of simple solution techniques.

Identification and classification of carcinogens: procedures of the Chemical Substances Threshold Limit Value Committee, ACGIH. American Conference of Governmental Industrial Hygienists.

The Chemical Substances Threshold Limit Value Committee of the American Conference of Governmental Industrial Hygienists has refined its procedures for evaluating carcinogens. Types of epidemiologic and toxicologic evidence used are reviewed and a discussion is presented on how the Committee evaluates data on carcinogenicity. Although it has not been conclusively determined whether biological thresholds exist for all types of carcinogens, the Committee will continue to develop guidelines for permissible exposures to carcinogens. The Committee will continue to use the safety factor approach to setting Threshold Limit Values for carcinogens, despite its shortcomings. A compilation has been developed for lists of substances considered to be carcinogenic by several scientific groups. The Committee will use this information to help to identify and classify carcinogens for its evaluation.

Determining “safe” levels of exposure: Safety factors or mathematical models?

The object of regulatory toxicology is to determine “safe” levels of human exposure to toxicants present in the environment. The traditional safety factor approach is compared to more recent mathematical modeling techniques, outlining the underlying assumptions and statistical properties of each procedure. Several linear extrapolation procedures are examined in detail using computer simulation, along with the impact of nonlinear kinetics on the extrapolation process.

Partial coefficient design in geotechnics : Semple, R M Ground Engng, V14, N6, Sept 1981, P47–48

The article briefly considers that the partial coefficient method, whereby partial safety factors are applied to the actual load and ultimate shear stress, may be unsuitable for geotechnical design and be of little benefit compared with the convention lumped safety factor approach. There is a greater chance of errors being introduced because there are more steps involved in the partial coefficient method. Safety factors are integrated into the analysis, tending to be geared to code requirements, reducing the understanding of geotechnical principles. Reliable information on safety is largely empirical and specific to certain problems. Any extrapolation to new conditions, using the partial coefficient method could produce errors. The use of probabilistic theory and statistics may cause major errors in selection of soil parameters since soil is not a manufactured material. The true measure of safety is the ease with which the excess of resistance over load is lost. Partial coefficients, specified in codes and incorporated into analyses may discourage proper depth of study in complicated problems. (TRRL)

On Probabilistic Design

The probabilistic approach to design is developed and contrasted with the conventional safety factor approach. A careful interpretation of random variable design inputs is given, leading to a statistical extreme-value model of loads. In addition to the “reliability” concept, the concept of “mission length” is explicitly introduced to the design process. A simple design problem, involving random variable loads and constant material properties, is solved and illustrated. Possible extensions of this design problem, and their likely difficulties, are indicated.

Reliability analysis of mechanical components and systems

A six-point comprehensive definition of reliability is given and discussed. A fifteen-step “Design by Reliability” methodology is presented and illustrated. Methods for synthesizing the failure governing stress and strength distributions, and for calculating the associated reliability, are presented and illustrated. A method for determining the lower, one-sided confidence limit of the calculated reliability is given and illustrated. The data requirements for this design methodology are discussed, and such data generated at the Reliability Research Laboratory of The University of Arizona are presented. The methodology is compared with the conventional safety factor approach and a unification of the statistical safety factor with the reliability is given.