Safety Factor Approach Research Articles

A comparison of the simplified probabilistic method in R6 with the partial safety factor approach

Probabilistic assessments are a useful aid to decision making in areas such as safety analysis, design studies and the deployment of resources on maintenance, inspection and repair. In principle, a full probabilistic assessment requires a complete knowledge of the relevant failure models and the distributions for each of the input quantities. However, in practice, these requirements cannot normally be met in full and it is necessary to employ various simplifying assumptions and approximations in order to make the analysis tractable. The partial factor method and the simplified approach in R6 provide two relatively simple and independent methods of assessing failure probabilities using R6. The two methods have been applied to a set of test cases and the results compared. In the case of the partial safety factor method target reliabilities in the range 10 −3–10 −5 were considered. Sets of partial safety factors for load, defect size, fracture toughness and yield stress were taken from BS 7910 and used for assessments covering different regions on the R6 failure assessment diagram. A calculation of the assessed failure probability was also carried out for each of these sets of conditions using a simplified probabilistic approach developed for the R6 procedure. The assessed failure probabilities were compared with the corresponding target reliability assumed for the partial safety factor calculation. It was found that the partial safety factor assessments were generally conservative compared to the simplified approach. However, in many instances the assessed probabilities were several orders of magnitude smaller than the target reliabilities suggesting that the recommended values of partial safety factors in BS7910 were excessively conservative for some of these conditions.

Generalizing the safety factor approach

Safety factors (uncertainty factors) are used to avoid failure in a wide variety of practices and disciplines, in particular engineering design and toxicology. Although these two areas have similar problems in their use of safety factors, there are no signs of previous communication between the two disciplines. The present contribution aims at initiating such communications by pointing out parallel practices and joint issues between the two disciplines. These include the distinction between probabilistic variability and epistemic uncertainty, the importance of distribution tails, and the problem of countervailing risks. In conclusion, it is proposed that future research in this area should be interdisciplinary and make use of experiences from the various areas in which safety factors are used.

Evidence of apoptotic effects of 2,4-D and butachlor on walking catfish, Clarias batrachus, by transmission electron microscopy and DNA degradation studies

Apoptosis or programmed cell death is characterized morphologically by chromatin condensation, cell shrinkage, fragmentation of the nucleus and cytoplasm, and consequently formation of apoptotic bodies. It has also been best characterized by the cleavage of DNA into nucleosomal size fragments of 180–200 bp or multiples of the same. Contrary to this, under extreme conditions, the cells were found to show adaptive response to apoptosis and unable to regulate their own death; necrosis is therefore predominantly observed. In the present study, we showed induction of apoptosis in Clarias batrachus due to sublethal concentration of 2,4-D and butachlor at multiple exposure time. The first phase of the study involved light microscopy (LM) and transmission electron microscopy (TEM) for ultrastructural abnormalities of the germinal tissues. While, in the second phase of the study, DNA degradation of blood and hepatic tissue was resolved on agarose gel electrophoresis. In histopathological studies, large numbers of stage II oocytes were noted for nuclear blebbing irrespective of the test chemical. Some of the butachlor-exposed oocytes showed vacuolation and electron dense cytoplasm along with thickened nuclear envelope, having close association with the lysosomes on the cytoplasmic side. Some oocytes undergo nuclear blebbing having inner dense core and translucent cytoplasm. Leydig cells were slightly hypertrophied and few appeared pycnotic, a process involving necrotic changes in which the cell nuclei were characterized by rounding up and condensation resulting in hyperchromatic staining or pycnosis. In testicular tissue, spermatogonial nuclei had irregular large clumps of heterochromatin adjoining the nuclear membrane indicating initial stage of apoptotic cell death. Electrophoretic separation resulted in a ladder pattern of blood DNA and smear like pattern of hepatic DNA. These results indicate that the above herbicides are able to induce apoptosis both at molecular as well as cytological level. A reference dose or safety factor approach to calculate risk of human exposure to both chemicals is still awaited.

Safety and Design of Vertical Breakwaters

The design of the breakwaters based on the current design manual in Hong Kong uses the overall safety factor approach. This approach, in general, does not provide a safety consistent design, and lacks the invariant property by using different definitions for load effects and resistance Identified through the rewriting of equilibrium equations. This study is focused on the selection of the design format to be used far designing vertical breakwaters subjeded to wave loading. The required caisson width of a vertical breakwater is evaluated using Coda’s formulas and different definitions of the overall safety factor. Also simple probabilistic analysis is carried out. The numerical results show that one should treat the wave induced load effects consistently in order to provide a more safety consistent design. Further, it is Indicated that the overall safety factor format in the current design manual for designing breakwaters can be modified into the so-called partial safety factor format. This modification do...

Distributions of Individual Susceptibility among Humans for Toxic Effects: How Much Protection Does the Traditional Tenfold Factor Provide for What Fraction of Which Kinds of Chemicals and Effects?

A significant data base has been assembled on human variability in parameters representing a series of steps in the pathway from external exposure to the production of biological responses: contact rate (e.g., breathing rates/body weight, fish consumption/body weight); uptake or absorption (mg/kg)/intake or contact rate; general systemic availability net of first pass elimination and dilution; systemic elimination or half-life; active site availability/general systemic availability; physiological parameter change/active site availability; functional reserve capacity--change in baseline physiological parameter needed to pass a criterion of abnormal function or exhibit a response. This paper discusses the current results of analyzing these data to derive estimates for distributions of human susceptibility to different routes of exposure and types of adverse effects. The degree of protection is tentatively evaluated by projecting the incidences of effects that would be expected for a tenfold lowering of exposure from a 5% incidence level if the population distribution of susceptibility were truly log-normal out to the extreme tails, and if the populations, chemicals, and responses that gave rise to the underlying data were representative of the cases to which traditional uncertainty factor is applied. The results indicate that, acting by itself, a tenfold reduction in dose from a 5% effect level is associated with effect incidences ranging from slightly less than one in ten thousand, for a median chemical/response, to a few per thousand, for chemicals and responses that have greater human interindividual variability than 19 out of 20 typical chemicals/responses. In practice, for many of the cases where the traditional tenfold factor is applied, additional protection is provided by other uncertainty factors. Nevertheless, the results generate some reason for concern that current application of traditional safety or uncertainty factor approaches may allow appreciable incidences of responses in some cases.

Background to the ADI/TDI/PTWI.

International scientific committees such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint FAO/WHO Meeting on Pesticide Residues (JMPR), regional scientific committees such as those of the European Union, and national regulatory agencies generally use the safety factor approach for establishing acceptable or tolerable intakes of substances that exhibit thresholds of toxicity. The acceptable daily intake (ADI) is used widely to describe "safe" levels of intake; other terms that are used are the reference dose (RfD) and tolerable intakes that are expressed on either a daily (TDI or tolerable daily intake) or weekly basis. JECFA uses the term PTWI, or provisional tolerable daily intake, for contaminants that may accumulate in the body. The weekly designation is used to stress the importance of limiting intake over a period of time for such substances. When using this approach no-observed-effect levels (NOELs) or no-observed-adverse-effect levels (NOAELs) are identified in the critical studies, to which appropriate safety or uncertainty factors are applied. Although the value of safety factors varies depending upon a number of factors, 100 is most often used, which is designed to account for interspecies and intraspecies variations. Within the framework of the IPCS project on harmonization of approaches to the assessment of risk from exposure to chemicals, issues relating to uncertainty and variability are being addressed with the aim of relying, whenever appropriate, on data-derived safety/uncertainty factors. The ILSI Europe ADI Task Force has, for the past few years, been considering the scientific basis for the safety factor, which will be discussed by other speakers in the workshop. The value of the NOAEL is dependent on the design of the study. Because of the expense and time required conduct many studies, doses are usually spread over wide intervals. Thus, the no-observed-adverse-effect level may be considerably less than a marginally effective dose. In addition, use traditionally has not been made of the dose-response relationship when establishing ADIs. Newer approaches such as the benchmark dose may provide ways of making use of dose-response information. It is unlikely that consumption at the level of the ADI will result in significant risk to the consumer because of the conservatisms that are built into it. It usually is based on long-term studies that are intended to mimic consumption over the lifetime of humans. The ADI is applied to "discretionary" chemicals (food additives, veterinary drugs, and pesticides) by JECFA and JMPR, which are relatively easy to control if safety problems are identified. On the other hand, when tolerable intakes are derived for contaminants that are present in the environment at high levels, the use of standard safety factors could result in discarding large portions of the food supply. Thus, it is very important that the basis for the tolerable intake is fully described so that informed judgments can be made about the health consequences of exceeding it.

The Probability of Death in the Room of Fire Origin: an Engineering Formula

The paper presents a partial safety factor approach to the problem of evaluating competing designs for fire safety in the room of fire origin in a building. A partial safety factor is defined as the ratio of the design value to the characteristic value for a load type variable and its inverse for a resistance type variable. The safety criterion considered is the expected number of deaths in the room or, alternatively, the probability of any death. A death is assumed to occur when the time, X between the occurrence of the alerting cue and the onset of untenable conditions is shorter than the time, Y to evacuation.First, a safety index, β is obtained, based on the means and standard deviations of the logarithms of X and Y. Partial safety factors for X and Y can then be calculated.It is further shown that there are theoretical reasons as well as empirical evidence for assuming that X and Y both have approximately a lognormal distribution. There is then a direct connection between the probability of death and...

Probabilistic Analysis of Exit Gradients due to Steady Seepage

The traditional approach for estimating the exit gradient \ii\i\de downstream of water retaining structures due to steady seepage is to assume homogeneous soil properties and proceed deterministically, perhaps using flow-net techniques. Once the exit gradient is estimated, a large safety factor of at least five or six is applied. The reason for this conservative approach is twofold. First, the consequence of piping and erosion brought about by \ii\i\de approaching and critical value \ii\i\dc can be very severe, leading to complete and rapid failure of civil engineering structures with little advance warning. Second, the high safety factors reflect the designer’s uncertainty in local variations of soil properties at the exit points and elsewhere within the flow domain. This paper presents an alternative to the safety factor approach by expressing exit gradient predictions in the context of reliability-based design. Random field theory and finite-element techniques are combined with Monte-Carlo simulations to study the statistics of exit gradient predictions as a function of soil permeability variance and spatial correlation. Both two- and three-dimensional boundary-value problems are considered. The approach enables conclusions to be drawn about the probability of critical conditions being approached and hence failure at a given site. The reliability approach is thought to represent a more rational methodology for guiding designers in the decision-making process.

Reliability-Based Design of Externally Pressurized Vessels

A reliability-based Level I design procedure is proposed for ring-stiffened cylindrical shells under external pressure. The main collapse modes and the present safety factor approach are reviewed. The major aspects involved in code development, such as the statistical properties of the basic variables, reliability methods, sensitivity studies, code format, target reliability, partial safety factor optimization, and comparison with the present practice are described. Safety margins for design are proposed which depend on the design pressure, maximum expected overdive, and shell slenderness. Some suggestions for future work are also given.

Structural adhesive bonded joints in engineering – drafting design rules

This paper introduces methods to draw up design rules to calculate the resistance of adhesive bonded joints for structural applications. In the past, design rules were based on allowable stresses, while the current rules verify limit states. Best known is the partial safety factor approach. This method enables to distinguish different reliability levels by using load and material factors. These factors take into account the stochastic nature of both load actions and resistance of a structure. In case of adhesive bonded joints also the durability effects have to be considered. To calibrate the partial safety factors both engineering judgement and probabilistic techniques can be used. Since the experience with design rules for structural adhesive bonded joints is limited, the use of probabilistic techniques seems to be a promising opportunity to draft design rules. To do this it is necessary to have a proper description of the nature of adhesive bonded joints. Special attention should be paid to the statistical distribution of the resistance and the effects of durability. An example of drafting a design rule illustrates the current possibilities. To conclude this paper guidelines are formulated how to draw up design rules.

Review of noncancer risk assessment: Applications of benchmark dose methods

The overall goal of this project is to evaluate and compare risk assessment methods traditionally used for noncancer health risks and to compare them with new approaches. These methods include the no observed adverse effect level (NOAEL), lowest observed adverse effect level (LOAEL), and the more recently proposed benchmark dose (BMD), in which a dose is identified using a curve‐fitting procedure and a prespecified effect level. Applications of the BMD method are reviewed for developmental toxicity, reproductive toxicity, neurotoxicity, ecological toxicity, carcinogenicity, and other biological impacts. Evaluations have shown that the benchmark method is generally no more conservative than the NOAEL approach and confers several significant advantages for safety assessment. In addition, traditional safety factor approaches used for RfD calculation based on LOAEL values are overly conservative. Studies show that exposures at NOAELs are not “risk free”; but may represent effect levels ranging from 3% up to 21%. An important advantage of BMD approaches is that regulatory limits can be consistently set at a given response level rather than being dictated by study design. BMD methodology also allows for easy transition to biologically based dose response modeling as such models are developed.

Risk Assessment of Inhaled Chloroform Based on Its Mode of Action

The development of scientifically sound risk assessments based on mechanistic data will enable society to better allocate scarce resources. Inadequate risk assessments may result in potentially dangerous levels of hazardous chemicals, whereas overly conservative estimates can result in unnecessary loss of products or industries and waste limited resources. Risk models are used to extrapolate from high-dose rodent studies to estimate potential effects in humans at low environmental exposures and determine a virtually safe dose (VSD). When information to the contrary is not available, the linearized multistage (LMS) model, a conservative model that assumes some risk of cancer at any dose, is traditionally employed. In the case of airborne chloroform, the dose at which an increased lifetime cancer risk of 10(-6) could be calculated was chosen as the target VSD. Applying the LMS model to the mouse liver tumor data from a corn-oil gavage bioassay yields a VSD of 0.000008 ppm chloroform in the air. The weight of evidence indicates that chloroform is not directly mutagenic but, rather, acts through a nongenotoxic-cytotoxic mode of action. In this case, tumor formation results from events secondary to induced cytolethality and regenerative cell proliferation. Toxicity is not observed in rodents when chloroform is not converted to toxic metabolites at a rate sufficient to kill cells. Thus, tumors would not be anticipated at doses that do not induce cytolethality, contrary to the predictions of the LMS model. Inhalation studies in rodents show no cytolethality or regenerative cell proliferation in mouse liver at a chloroform concentration of 10 ppm as the no observed effect level (NOEL) or below. Using that NOEL and a safety factor approach, one can develop a VSD of 0.01 ppm. Integrating these data into the risk assessment process will yield risk estimates that are appropriate to the route of administration and consistent with the mode of action.

Effects of pesticide mixtures at the acceptable daily intake levels on rat carcinogenesis

Possible modifying effects of pesticide mixtures on tumorigenesis were investigated with medium-term carcinogenesis protocols for rapid detection of carcinogenic agents using male F344 rats. In the 8-wk liver model, administration of 20 pesticides (19 organophosphorus compounds and one organochlorine), added to the diet each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of these 20 pesticides at 100 times the ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 wk, mixtures of 40 pesticides (high production examples) or 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not modulate carcinogenesis in any organ initiated by five known potent carcinogens in combination. These results thus provide direct support for the safety factor (usually 100) approach using ADI values for the quantitative risk evaluation of pesticides. Copyright ¢ 1997 Elsevier Science Ltd.

Evolution and current status of neurotoxicity risk assessment.

The U.S. EPA neurotoxicity risk assessment guidelines define neurotoxicity as the capacity of chemical, biological, or physical agents to cause an adverse functional or structural change in the peripheral or central nervous system. Chemical-induced changes in the structure or persistent changes in behavior, neurochemistry, or neurophysiology of the nervous system are regarded as neurotoxic effects. Reversible effects occurring at doses that could endanger performance in the workplace, are associated with a known neurotoxicological mechanism of action, covary with a known neurotoxicological effect, or are latent effects uncovered by pharmacological or environmental challenge, could be considered to be neurotoxic effects. It should also be noted that even if a chemical-induced change in neurobiological function or structure does not meet the criteria established for a neurotoxic effect, the alteration could still be considered as adverse and used in a regulatory decision. Adverse effects detected by neurobiological procedures should not, however, necessarily lead to the conclusion that the chemical is a neurotoxicant. At the present time,the default RfD uncertainty factor approach is used for neurotoxicological data. A number of other safety factor approaches and quantitation dose-response models have been proposed for evaluating neurotoxicological data. However, a very limited number of comparisons have been made between the RfD approach and alternatives. In summary, neurotoxicity is one of several noncancer and points currently being used by regulatory agencies. The effective utilization of neurobiological measures to assess chemical-induced changes in the structure and function of the nervous system depends on properly designed studies and elimination of potential confounding variables that obscure interpretation of data from toxicological studies.

Lack of carcinogenicity of pesticide mixtures administered in the diet at acceptable daily intake (ADI) dose levels in rats

Carcinogenic effects of pesticide mixtures were examined with our medium-term carcinogenesis protocols using male F344 rats. In the 8-week liver model, combined dietary administration of 20 pesticides (19 organophosphorus compounds and 1 organochlorine), each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 weeks, mixtures of 40 pesticides (high volume compounds) and 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not enhance carcinogenesis in any organ initiated by 5 different known carcinogens in combination. These results provide support for the safety factor (usually 100) approach presently used for the quantitative hazard evaluation of pesticides.

Negative selection in hepatic tumor promotion in relation to cancer risk assessment

Mechanistic studies with phenobarbital (PB), 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and other liver tumor promoters support a general model of promotion involving negative selection where specifically-mutated cells derive a growth advantage in the presence of persistent mitosuppression. Exposure to these liver tumor promoters appears to transiently enhance hepatocyte replication, presumably via transcriptional activation of growth regulatory genes, leading to a homeostatic increase in mitoinhibitory growth factors in the liver to constrain proliferation. Transforming growth factor beta 1 (TGF-β), a potent mitoinhibitory growth factor for hepatocytes, has been associated with the mitosuppression caused by PB and certain peroxisomal proliferators. Escape from TGF-β mitosuppression may involve loss or alteration of function of the mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor, which is required for TGF-β 1 activation, or alterations of the TGF-β types I, II and III signal transduction receptors. A risk assessment based on a negative selection mechanism could be conducted for tumor promotion endpoints with TCDD and compared with current approaches that implicitly regard TCDD as an initiator. Benchmark dose calculation using centrilobular induction of cytochromes P450 1A1 and 1A2 as a surrogate for periportal growth stimulation would provide a rational starting point for application of conventional safety factor approaches, similar to those used with non-cancer effects. In the future, tissue and plasma concentrations of specific growth factors e.g. TGF-β or hepatocyte growth factor, HGF, might be considered as more direct dose surrogates for tumor-promoting effects of xenobiotics. Uncertainty factor adjustments to a TCDD benchmark dose calculation should eventually rely on direct knowledge of regulation of specific growth regulatory genes and their receptors in relevant species and on species differences in TCDD pharmacokinetics, instead of application of default animal-to-human and interindividual uncertainty factors.

Effect of ingestion of 20 pesticides in combination at acceptable daily intake levels on rat liver carcinogenesis

Exposure of agricultural workers and the general population to pesticides is a major concern, and possible summation or synergistic effects deserves particular attention. In this study, however, combined dietary administration of 19 organophosphorus compounds and one organochlorine pesticide, each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by d iethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of lesions. The results thus provide direct support for the present safety factor approach to the quantitative hazard evaluation of pesticides.

Nonlinearity of dose-response functions for carcinogenicity.

Carcinogenesis data for 315 chemicals were obtained from the National Cancer Institute-National Toxicology Program (NCI-NTP) bioassay programs and were analyzed to examine the shape of carcinogenesis dose-response curves. Tumor site data were more often consistent with a quadratic response than with a linear response, suggesting that the routine use of linear dose-response models will often overestimate risk. Information from in vivo short-term mutagenicity and genotoxicity assays was also obtained for most of these rodent bioassays. It was found that there were no clear relationships between the shape of the carcinogenesis dose-response curve and the result of the short-term test. These observations argue against the concept that carcinogens that are positive in a short-term assay be regulated using a linear dose-response curve and those that are negative be regulated using a sublinear dose-response curve or a safety factor approach.

Studies on the prenatal toxicity of toluene in rabbits following inhalation exposure and proposal of a pregnancy guidance value.

Prenatal toxicity of toluene was determined in two separate studies by inhalation exposure of Himalayan rabbits. In the first study 15 artificially inseminated females per group were exposed to 30, 100, or 300 ppm and in the second study 20 artificially inseminated females per group inhaled 100 or 500 ppm. In each case the rabbits were exposed for 6 hours per day from day 6 post-insemination (p.i.) to day 18 p.i. The respective controls inhaled conditioned clean air under the same exposure conditions. No signs of maternal toxicity were observed. All data obtained on gestational parameters were found to be within the variation range reported for this rabbit strain. The fetal external, soft tissue and skeletal findings were seen in toluene exposed fetuses in a frequency similar to the corresponding and/or historical controls. Differences observed between the groups were not concentration dependent and were considered incidental rather than compound related. Therefore, toluene was not embryotoxic, fetotoxic, or teratogenic for rabbits exposed during the period of organogenesis. The highest concentration tested under these conditions (500 ppm) was found to be a no-observable-adverse-effect level (NOAEL) for both the adult and the fetal Himalayan rabbit. Based on these and previous results of animal studies of prenatal toxicity, a safety or uncertainty factor approach is considered for setting limits of exposure for women at workplaces. A pregnancy guidance value of 20 ppm is proposed.

Between science and politics: assessing the risks of dioxins in Canada and the United States

The history of U.S. and Canadian risk assessments for dioxin is an increasingly familiar tale of debates within the scientific community played out in the political arena. Uncertainty among scientists creates the possibility of large disparities between different governments' policies. However, the pattern of differences that emerges reflects the context in which science policy decisions are made within each agency and within each country. The political environment has implications not just for how ‘mandated science’ is received, but for how it is conducted. Many features of the dioxin case are consistent with observations by others. In the cases of formaldehyde, alachlor, alar, and amaranth, EPA relied on mathematical models to assess the risks of potential carcinogens, while Health and Welfare Canada relied on the more traditional safety factor approach.35 This body of evidence is suggestive of national styles of ‘transscience.’ Features of the U.S. style include explicit rationales for regulatory decisions, reliance on consistent and explicit risk assessment principles, and public debate over scientific aspects of public policy. The Canadian style is exemplified by closed decisionmaking, case-by-case review, and the absence of public discussion of the scientific basis for government decisions. The differences between FDA and EPA in this case study suggest an important caveat, however. The ‘U.S. style’ is most clearly reflected in the implementation of the non-discretionary environmental, health and safety statutes passed by the U.S. Congress since 1970. More closed and traditional styles of regulatory decisionmaking may survive within the U.S. as vestiges of a more deferential past. Even less than ‘pure’ science, ‘trans-science’ is not a universal enterprise. When scientists do reach agreement, it can be a powerful force that can even overcome political and national differences (Haas, 1989). However, when science is uncertain, as is typically the case in assessing the risks of toxic chemicals, there is more room for political factors to shape the way different countries interpret science in making policy decisions.