ISSN:0265-203X    

DOI:10.1080/02652039309374151

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

A safety factor of 100‐fold is commonly applied to animal data to derive the acceptable daily intake (ADI) of food additives; other factors have been used in some cases and higher values are used more frequently for determining the tolerable daily intake (TDI) of environmental chemicals. The 100‐fold factor is considered to represent the product of a 10‐fold factor to allow for species differences between the test animal and humans and a 10‐fold factor to allow for inter‐individual differences. A scheme is proposed whereby data relevant to the safety assessment of a compound, e.g. species differences in toxicokinetics, can contribute quantitatively to the safety factor and therefore to the ADI or TDI. For this to be possible, it is necessary to subdivide each of the 10‐fold factors into two separate factors to allow for differences in toxicokinetics and toxicodynamics. For any compound, data on one particular aspect may be used to derive a specific data‐derived factor for that aspect. The overall safety factor will then be calculated as the product of the known data‐derived factor(s) and default values for the remaining unknown factors. In this way the derivation of the safety factor would be clearly defined and the potential impact of additional data on other aspects identified. Additional safety factors (over and above the 100‐fold or overall data‐derived factor) are also proposed to allow for the nature or severity of the toxicity and the adequacy of the database. These factors are consistent with previous evaluations and will allow the logical derivation of factors greater than either 100 or the appropriate data‐derived factor. These additional factors will be of greatest value in the derivation of safety factors for the calculation of the TDIs of environmental contaminants but may also be applied if necessary to the safety assessment of food additives. In such cases the rationale and logic for a safety factor in excess of 100 will be clearly defined.

ISSN:0265-203X    

DOI:10.1080/02652039309374152

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

The principles of ‘data‐derived safety factors’ are applied to toxicological and biochemical information on butylated hydroxyanisole (BHA). The calculated safety factor for an ADI is, by this method, comparable to the existing internationally recognized safety evaluations. Relevance for humans of forestomach tumours in rodents is discussed. The method provides a basis for organizing data in a way that permits an explicit assessment of its relevance.

ISSN:0265-203X    

DOI:10.1080/02652039309374153

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

Erythrosine (FD & C Red No.3) is an iodine‐containing food colour which was used as an example in the application of the proposed approach of data‐derived safety factors. The effect of erythrosine on the thyroid and the mechanism by which the effect is induced has been central to the discussion of the establishment of an Acceptable Daily Intake (ADI), or not, and a short account is given of the effect of erythrosine on the thyroid. The evaluation of erythrosine as a secondary tumorigenic agent was based on the evaluations of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Scientific Committee for Food of the Commission of the European Communities (SCF). In the proposed decision tree scheme, three different possibilities were examined. One was based on the long‐term data and the second on the hormone data in the rat; the third was based on the NOEL for hormonal changes in humans. The three approaches with different NOEL and default values resulted in the following ADIs: 0.25, 0.3 and 0.1 mg/kg bw. The cases are discussed and it is concluded that the ADI based on the NOEL in human studies seems most appropriate. As there is most uncertainty about the default value for human pharmacokinetic variability, it is suggested that further human studies might elucidate this point.

ISSN:0265-203X    

DOI:10.1080/02652039309374154

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

Exposure to lead (Pb) continues to be a source of concern for the US Food and Drug Administration and other United States federal regulatory agencies. Blood lead levels as low as 10μg/dl have been associated with impaired neurobehavioural and cognitive development and electrophysiological deficits in children and reduced gestational age and birth weight in infants. Blood lead levels of 10μg Pb/dl are also of concern in pregnant women because of exposure to the fetus. Blood lead levels of 30μg Pb/dl have been associated with elevated blood pressure and other adverse effects in adults. Thus, the values of 10 and 30μgPb/dl represent lowest‐observed‐effects levels for developing and adult populations, respectively. The ingestion levels that result in these blood levels of concern were estimated to be 60μg Pb/day for children ages 6 years or younger, 150μg Pb/day for children aged 7 years or older, 250μg Pb/day for pregnant women and 750μgPb/day for adults. Provisional total tolerable intake levels for lead were derived from these blood lead levels for each group by applying the Renwick approach to obtain a tolerable exposure level.

ISSN:0265-203X    

DOI:10.1080/02652039309374155

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

An increased incidence of bladder cancer is found when male rats are fed high dietary concentrations of sodium saccharin (3% or more) from birth. This toxicity has been used as the basis for the development of a data‐derived safety factor. Such an effect would attract an extra factor (10‐fold) for nature of toxicity and in the absence of other data would result in a high overall safety factor. However the extensive mechanistic database on sodium saccharin allows an assessment of the potential relevance of the effect for humans. In addition the effect is only seen under specific conditions in rats, i.e. largely with the sodium salt and with a commercial rat diet. The effect is not related to the concentration of saccharin in the rat urine or bladder so that toxicokinetic considerations are simplified. The extensive animal database allows the determination of data‐derived factors for inter‐species differences in both toxicokinetics and toxicodynamics. Based on this analysis an overall safety factor of 50 (which includes the factor of 10 for severity of effect) would appear appropriate at the present time. This factor, and the ADI which would result from its application, are consistent with the absence of an association between the consumption of artificial sweeteners and bladder cancer in humans.

ISSN:0265-203X    

DOI:10.1080/02652039309374156

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

In this report the evaluation of a safety factor is assessed, according to the decision tree suggested by Renwick (1991a,b), to determine a Tolerable Daily Intake (TDI) value for the environmental contaminant bis(tri‐n‐butyltin)oxide (TBTO). Based on available literature the nature of the most sensitive parameter of TBTO‐toxicity was perceived to be on lymphoid organs and lymphoid function. Subsequently, safety factors were derived in relation to published data on inter‐species and inter‐individual differences in both kinetics and dynamics of TBTO.

ISSN:0265-203X    

DOI:10.1080/02652039309374157

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

Diethylhexylphthalate causes peroxisome proliferation and is hepatocarcinogenic in rodents; it also displays reproductive and developmental toxicity in a variety of mammalian and non‐mammalian species. These manifestations of toxicity have each been separately evaluated for the development of a data‐derived safety factor and Tolerable Daily Intake (TDI). Using hepatocarcinogenicity as the pivotal study, the nature of toxicity factor of 10 is applicable and there are no adequate studies demonstrating a No‐Observed‐Adverse‐Effect Level (NOAEL). If studies of less statistical sensitivity are used to derive the NOAEL and a factor of 0.1 is used for the relative sensitivity to humans of peroxisome proliferation (assuming this is linked mechanistically to carcinogenesis), a TDI of 1 mg/kg bw is obtained. The data‐derived safety factor using peroxisomal proliferation as the pivotal end‐point is 6.25, since the factor from trans‐species toxicodynamics is 0.01, and the TDI derived from the NOAEL for peroxisome proliferation is thus 8 mg/kg bw. If teratogenicity is used as the pivotal study, the nature of toxicity attracts a factor of 10 and all the other aspects take default values because of the limited availability of relevant toxicodynamic and toxicokinetic data. The TDI derived from the NOAEL for teratogenicity is then 0.04 mg/kg bw and this confirms teratogenicity as the limiting aspect of toxicity defining the TDI. It also identifies the fact that appropriate toxicokinetic and toxicodynamic data related to the pregnant animal and fetus would facilitate a reevaluation of the safety factor and TDI by replacing the current default values by data‐derived values.

ISSN:0265-203X    

DOI:10.1080/02652039309374158

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

ISSN:0265-203X    

DOI:10.1080/02652039309374150

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor