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The toxicological assessment of chemically complex food matrices (CCFM) usually is very time consuming, expensive and uses many animal studies. Improvements to obtain a more efficient assessment process remain limited as long as we retain traditional approaches to toxicological risk assessment. New concepts would be needed to achieve real innovations in risk assessment. The threshold of toxicological concern (TTC) potentially is such a concept that has existed for many years and recently has been further developed. The safety of CCFM is difficult to assess as there are numerous unknown substances present (often referred to as 'Forest-of-Peaks' in chromatographic analysis). Usually, for the evaluation of CCFM, a full safety assessment approach involving animal studies is needed, but the exposure to most substances is low and TTC might be applicable. However, to apply TTC efficiently to CCFM, a strategy is needed to deal with large numbers of unknowns (substances of which structural information is lacking). Therefore, we have drafted a framework for application of TTC in safety assessment of CCFM. This paper describes the criteria and development of the framework proposing a stepwise approach for the application of TTC in safety assessment of CCFM and future developments required.

Objectives: The critical health effects of formaldehyde exposure include sensory irritation and the potential to induce tumours in the upper respiratory tract. In literature, a concentration as low as 0.24 ppm has been reported to be irritating to the respiratory tract in humans. Nasal tumour-inducing levels in experimental animals seem to be 1-2 orders of magnitude larger. In this paper, the subjectively measured sensory irritation threshold levels in humans are discussed in line with findings obtained in animal experiments. In addition, a Benchmark dose (BMD) analysis of sensory irritation was used to estimate response incidences at different formaldehyde concentrations. Methods: Data on respiratory irritation and carcinogenicity of formaldehyde were retrieved from public literature and discussed. BMD analysis was carried out on human volunteer studies using the US-EPA BMD software. Results: Subjective measures of irritation were the major data found in humans to examine sensory (eye and nasal) irritation; only one study reported objectively measured eye irritation. On a normalized scale, mild/slight eye irritation was observed at levels ≥1 ppm, and mild/slight respiratory tract irritation at levels ≥2 ppm. With the BMD software, it was estimated that at a level of 1 ppm, only 9.5% of healthy volunteers experience 'moderate' (i.e., annoying) eye irritation (95% upper confidence limit). An important factor modulating the reported levels of irritation and health symptoms most probably includes the perception of odour intensity. In several studies, the 0-ppm control condition was missing. From the results of the long-term inhalation toxicity studies in experimental animals, a level of 1 ppm formaldehyde has been considered a NOAEL for nasal injury. Conclusions: Sensory irritation is first observed at levels of 1 ppm and higher. From both human and animal studies, it was concluded that at airborne levels for which the prevalence of sensory irritation is minimal both in incidence and degree (i.e.

Health risks resulting from occupational exposure to chemicals are controlled by the establishment of acceptable dermal and respiratory exposure levels. Due to a lack of route-specific toxicity data, acceptable levels are frequently established by means of route-to-route extrapolation. A pitfall in route-to-route extrapolation is the occurrence of local effects. Often, the results of acute irritation studies are used to assess the likelihood of the occurrence of local effects also following repeated exposure and thereby the validity of route-to-route extrapolation. We questioned this working practice and considered whether local effects observed in a given study are of any predictive value with respect to the occurrence of local effects after repeated exposure. Our database analysis indicates that substances inducing skin and/or eye irritation frequently induce local effects after repeated respiratory exposure. In contrast, observations made in any type of study show little or no positive predictive value for the occurrence of local effects after repeated dermal exposure. Notably, the absence of any indication of local effects in any type of study does not exclude the occurrence of local effects on repeated dermal or respiratory exposure. We conclude that the presumed reliability of route-to-route extrapolation in the absence of route-specific toxicity data can be questioned.

Assuming that temporal fluctuations in physiological parameters (e.g. haematology, biochemistry) in individual healthy non-exposed animals are non-adverse, the minimal magnitude of the Critical Effect Size (CES) for a number of continuous parameters of toxicity studies was derived. A total of 36 studies (19 pharmaceutical preclinical studies in dogs and 17 chemical risk assessment studies in rats) were analysed to determine within-animal variation in their control groups. Minimal CES-values were derived for each group of studies, differentiating where necessary between strains and sexes, using the 2.5 percentile (lower limit) and/or 97.5 percentile (upper limit) of the distribution of the within-animal variation around the mean of each parameter. We concluded that minimal CES-values for continuous clinical chemistry and haematology parameters should be established separately per species, strain, sex and study duration investigated. Grouping of minimal CES-values, leading to more or less "general" values, seems possible for those parameters that are subject to tight homeostatic control and consequently show little within-animal variation. Nearly a quarter of the proposed CES-values is ≤5%, nearly a quarter range from 6% to 10%, a quarter is 15% or 20%, and nearly 30% of the proposed values is ≥20% of the mean of the control animals. © 2009 Elsevier Inc. All rights reserved.

In this study, the within-animal variation in routinely studied continuous toxicological parameters was estimated from temporal fluctuations in individual healthy nonexposed animals. Assuming that these fluctuations are nonadverse, this within-animal variation may be indicative of the minimal magnitude of the critical effect size (CES). The CES is defined as the breaking point between adverse and nonadverse changes in a continuous toxicological parameter, at the level of the individual organism. The total variation in the data from individual nonexposed animals was divided in variation parts due to known factors (differences in sex, animal, and day) and a residual variation, by means of analysis of variance. Using the residual variation and the estimated analytical measurement error of a toxicological parameter, the within-animal variation can be estimated. The data showed within-animal variations ranging between 0.6% and 34% for different clinical chemistry and hematological parameters in 90-day rat studies. This indicates that different (minimal) CES values may be applicable for different parameters. © 2006 Society for Risk Analysis.

Due to a lack of route-specific toxicity data, the health risks resulting from occupational exposure are frequently assessed by route-to-route (RtR) extrapolation based on oral toxicity data. Insight into the conditions for and the uncertainties connected with the application of RtR extrapolation has not been clearly described in a systematic manner. In our opinion, for a reliable occupational health risk assessment, it is necessary to have insight into the accuracy of the routinely applied RtR extrapolation and, if possible, to give a (semi-)quantitative estimate of the possible error introduced. Therefore, experimentally established no-observed-adverse-effect-levels for inhalation studies were compared to no-adverse-effect-levels predicted from oral toxicity studies by RtR extrapolation. From our database analysis it can be concluded that the widely used RtR extrapolation methodology based on correction for differences in (estimates of) absorption is not generally reliable and certainly not valid for substances inducing local effects. More experimental data are required (from unpublished data or new experiments) to get insight into the reliability of RtR extrapolation and the possibility to derive an assessment factor to account for the uncertainties. Moreover, validated screening methods to predict/exclude the occurrence of local effects after repeated exposure are warranted. Especially, in cases where chemical exposure by inhalation or skin contact cannot be excluded route-specific toxicity studies should be considered to prevent from inadequate estimates of human health risks. © 2003 Elsevier Inc. All rights reserved.

The general goal of this discussion paper is to contribute toward the further harmonization of human health risk assessment. It first discusses the development of a formal, harmonized set of assessment factors. The status quo with regard to assessment factors is reviewed, that is, the type of factors to be identified, the range of values assigned, as well as the presence or absence of a scientific basis for these values. Options are presented for a set of default values and probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabilistic distributions of assessment factors are also described. Second, the effect parameter, the no-observed-adverse-effect level (NOAEL), is discussed. This NOAEL as selected from the toxicological database may be a poor substitute for the unknown, true no-adverse-effect level (NAEL). New developments are presented with respect to the estimation of the NAEL. The already widely discussed Benchmark Dose concept can be extended to obtain an uncertainty distribution of the Critical Effect Dose (CED). This CED distribution can be combined with estimated uncertainty distributions for assessment factors. In this way the full distribution of the Human Limit Value will be derived and not only a point estimate, whereas information on dose-response relations is taken into account. Finally, a strategy is proposed for implementation of the new developments into human health risk assessments.