Interpretation
David Woolley, Adam Woolley in Practical Toxicology, 2017
One of the reasons for looking for difference is the perceived obligation to show toxicity at one dose and thereby imply safety at a lower one. This leads to pressures to assign significance or otherwise to trivial differences; we must show toxicity, so this is a significant toxicological change. Or we must show a no-observed-effect level (NOEL), so this small difference at the bottom end of the dose–response curve is irrelevant. Although it has been pointed out that, to demonstrate a NOEL, there must be effects at higher doses, this edges toward irrelevance when the doses are vastly higher than those expected in humans. Where there is a small difference at the lowest dose level, which is supported by increasing differences at higher doses, it cannot be escaped that treatment has probably had an effect (or at least an influence) at the lowest dose. The significance of this difference is where interpretation becomes more complex. The no-adverse-effect level (NOAEL) is a useful concept because it acknowledges the presence of treatment-related change while putting it into perspective. The problem is that difference from controls, which is inevitable when using biological systems, is open to misinterpretation unless it is barn-door obvious, as shown by the very obvious test referred to above. For small differences, it is difficult to assign significance.
Quantitative Cancer Risk Assessment
Peter G. Shields in Cancer Risk Assessment, 2005
Several other procedures have been used for dose-response extrapolation, which lead to widely differing estimates of potency. The model with the most significant departure from the LMS model is the threshold model, which assumes that no significant risk is present below an identified exposure. In this model, a no-observed-adverse effect level (NOAEL) is determined, which serves a point of departure for the development of an acceptable dose. The NOAEL approach has been used extensively along with safety or uncertainty factors for the determination of acceptable doses for toxic effects other than cancer. However, this procedure has also been used by some European nations and on a limited basis in the United States where the chemical is believed to produce neoplasia by a process that involves a threshold (12). The major determinant for the use of a threshold model for a chemical is the lack of DNA reactivity coupled with a plausible explanation, such as chronic toxicity of the target organ, as the basis for the tumorigenic response.
Classification and management of toxicant-related information
Stanley Berent, James W. Albers in Neurobehavioral Toxicology, 2012
The Environmental Protection Agency (EPA) has worked with science and industry in attempts to develop systems to classify substances in terms of their relative toxicity. A No Observed Adverse Effect Level (NOAEL), for instance, is required of all commercially produced agents designed for use as pesticides or related applications (EPA, 1991). The NOAEL is defined as the highest dose that does not lead to an adverse effect. For non-carcinogenic substances (carcinogens have different regulatory requirements), the NOAEL is to be established through regulated methods of experimentation. To determine the allowable ‘safe dose’, the EPA adjusts the established NOAEL by dividing by a safety factor (SF) or uncertainty factor (UF). The SF is usually a factor of ten to account for possible differences in sensitivity between animals and humans and another ten for possible individual variations in sensitivity, a total SF = 100, or an assumed ‘no or negligible’ risk level of NOAEL/100 (Gaylor & Slikker, 1992).
Metabonomics analysis of liver in rats administered with chronic low-dose acrylamide
Published in Xenobiotica, 2020
Yanli Liu, Ruijuan Wang, Kai Zheng, Youwei Xin, Siqi Jia, Xiujuan Zhao
Our previous metabonomics analysis of rat urine suggested that exposure to AA caused liver damage in rats (Shi et al., 2017), but the mechanism of AA-induced effects on the liver are still unclear. No observed adverse effect level (NOAEL) is defined as “the highest level of continual exposure to a chemical that causes no significant adverse effect on the morphology, biochemistry, functional capacity, growth, development or life span of individuals of the target species used in the study”, which is obtained using traditional toxicology methods (Du et al., 2013; van Ravenzwaay et al., 2014). It was reported by the JECFA at its 72th meeting that the NOAEL of AA for a non-carcinogenic end-point was 0.2 mg/kg bw per day. This end-point was based on the induction of morphological nerve changes in rats following administration of AA in drinking-water for 90 days (WHO, 2010). In view of the characteristic advantages of metabonomics, a liver metabonomics study was performed using ultraperformance liquid chromatography–mass spectrometry (UPLC-MS) combined with multivariate statistics, including principal components analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), to investigate whether chronic exposure to AA at NOAEL (WHO, 2010) can induce toxicity in rat liver at the body metabolism level. At the same time, we utilized UPLC-MS metabonomics platform to identify AA-induced metabolic signatures of liver in rats and explore the mechanism of the effects. Furthermore, liver histopathology examination and anti-oxidation indices were conducted to verify the results of metabonomics.
Is current risk assessment of non-genotoxic carcinogens protective?
Published in Critical Reviews in Toxicology, 2018
Hedwig M. Braakhuis, Wout Slob, Evelyn D. Olthof, Gerrit Wolterink, Edwin P. Zwart, Eric R. Gremmer, Emiel Rorije, Jan van Benthem, Ruud Woutersen, Jan Willem van der Laan, Mirjam Luijten
For pesticides, a HBGV of a NGTXC like the acceptable daily intake (ADI) is based on the No-Observed-Adverse-Effect-Level (NOAEL), often derived from a 2-year carcinogenicity study (EC 2009, 2013). For pharmaceuticals, risk assessment first will take into account the presumed mode-of-action, in many cases related to its pharmacodynamic effect (van der Laan, Buitenhuis, et al. 2016; van der Laan, Kasper, et al. 2016). For chemicals that are within the scope of REACH the HBGVs of NGTXCs are based on the NOAEL derived from a subchronic toxicity study (van Leeuwen and Vermeire 2007; ECHA 2012) in the absence of a chronic toxicity/carcinogenicity study. The NOAEL is a dose for which it is usually assumed that the adverse effect is absent, because adverse effects are not observed in a particular study. However, adverse effects may be present, but at a magnitude that is not observable given the statistical power of the specific study. Reviews of large collections of datasets have demonstrated that a NOAEL, on average over a large number of toxicity studies, relates to around a 5% or 10% change in response (EFSA 2009). If such changes would occur at the NOAEL for the toxic endpoint that underlies cancer it cannot be a priori stated that the cancer risk will be zero. The question arises what the level of cancer risk might be, and whether this level is considered acceptable. The acceptability of the risk level is determined by risk managers and policy makers, and will most likely be based on discussions with various stakeholders.
An update on the hazard of and exposure to diethyl hexyl phthalate (DEHP) alternatives used in medical devices
Published in Critical Reviews in Toxicology, 2020
Shalenie P. Den Braver-Sewradj, Aldert Piersma, Ellen V. S. Hessel
SCENIHR and Danish EPA have published the critical NOAELs for the DEHP alternatives (Tables 5 and 6), these are generally higher than for DEHP and associated with nonreprotoxic effects. The newly published literature studies do not give reason for reconsideration of NOAELs determined by SCENIHR, because for most compounds the studies available are from insufficient quality, no adverse effects are measured or the effect doses are higher than the current NOAEL (Table 6). With the exception of BTHC and COMGHA (based on oral studies) and the uncertain results of DINCH, all the other considered plasticizers can cause reproductive toxicity. This occurs at dosages several fold higher than DEHP and equal or higher than their respective critical endpoints. Additionally, ANSES concluded in a recent review that DINCH does not cause reproductive and developmental toxicity effects. However, based on various effects on the thyroid, DINCH may have ED activity (ANSES 2016a). Danish EPA noted that the available data on DINCH did not indicate a need for further testing. In the present review, no additional data on endocrine activity of the alternatives were found.
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