- Email: [email protected]
Diapered skin and diaper dermatitis: Implications for risk assessment
Abstracts / Toxicology Letters 238S (2015) S32–S55
W12-4 Diapered skin and diaper dermatitis: Implications for risk assessment S. Felter Procter & Gamble, Central Product Safety, Mason, OH, United States Infant skin in the nappy area is recognized as having characteristics that potentially warrant special consideration in risk assessment. This is a result of the area being covered with a semiocclusive diaper which can lead to increased hydration of the skin. In addition, contact with urine and feces occurs frequently and can contribute to nappy dermatitis, which is most commonly seen in infants 6–12 months old. While modern diapers have led to a reduction in the frequency of nappy dermatitis, it is still a relatively common occurrence, although episodes of diaper rash are generally short-lived. Because diaper rash is associated with a disruption of skin barrier properties, it can result in greater penetration of chemicals through the skin, which must be considered in the safety assessment of any products used in the nappy area. The magnitude of this impact is expected to vary, depending on the extent and severity of the rash and the physical-chemical properties of the chemical in contact with the skin. For some chemicals, the impact will be negligible. For others, the impact might be greater but it will only be for a short period of time as the duration of diaper rash events is typically only a few days. This talk will provide an up-todate evaluation of the frequency, severity, and duration of diaper rash, and how this can impact overall exposure to chemicals with a range of physical–chemical characteristics. It is concluded that the overall impact is generally quite small and that current risk assessment methods are adequately protective, even when one considers the potential for occasional diaper rash. http://dx.doi.org/10.1016/j.toxlet.2015.08.142
W12-5 Quantitative Risk Assessment in the EU of Cosmetics for Babies and Children V. Rogiers Vrije Universiteit Brussel, In Vitro Toxicology and Dermato-Cosmetology, Brussels, Belgium The safety of cosmetics in the EU is regulated by Regulation 1223/2009 and is based on safe ingredients. It also applies for cosmetics of babies/children. Two channels are in place: (i) one functions under DG SANTE through the Scientific Committee on Consumer Safety (SCCS) and is concerned with Annex ingredients, composed of prohibited (II) and restricted substances (III), colorants (IV), preservatives (V) and UV-filters (VI); (ii) a second safety layer consists of risk assessment by the industry and concerns all finished products with their composing ingredients. In both channels, risk characterization of a substance is a combination of hazard identification, dose response and exposure assessment. Since March 2013, only animal-free validated methods may be applied. This creates a major challenge. Although for most endpoints of local toxicity and short-term exposure validated alternatives exist, this is not true for long-term tests e.g. repeated dose toxicity and developmental toxicity, carcinogenicity and toxicokinetics. The former tests are crucial as they usually deliver the No Observed Adverse Effect Level (NOAEL)-values, used in the calculation of the margin of safety (MoS = NOAEL/SED > 100, SED being the systemic exposure dose). 100 = 10×10 represents the inter-species × intra-species safety fac-
S51
tor. As “babies” are developing organisms, age is crucial and various stages of immaturity and maturation need to be considered at the anatomical and functional level. Also, clear definitions should be established. The intra-species factor of 10 is high enough in case of intact skin, but additional factors may be required for damaged skin as could occur in the nappy area (young babies, specific conditions of napkin dermatitis). Also infections need to be considered. Special concern has been expressed for adequate sun protection. 18 g/day, the exposure value used today in MoS-calculations, was found to be protective for babies/children. http://dx.doi.org/10.1016/j.toxlet.2015.08.143 Workshop W13: Non-Monotonic Dose–Response Curve in Hormonally Active Substances W13-1 Dose-response relationship: Monotone vs non-monotone curve E. Testai Istituto Superiore di Sanità, Environment and Primary Prevention, Rome, Italy Many chemicals are able to interfere with the complex endocrine network. Some interactions produce an homeostatic or adaptive response which cannot be considered adverse unless the so called “threshold of adversity” is exceeded. Endocrine disruptors (ED) acts with different mode of action which should be biological plausible; potency and causal relationship should also be taken into account. Regarding ED there is a strong debate about the ‘low dose hypothesis’, according to which low dose effects, not present at higher doses, may display a non-monotonic dose-response (NMDR). In the case of a NMDR curve the traditional NOAEL/BMDL point of departure cannot be used to derive a health-based guidance value. Indeed, the paradigm in risk assessment is that the individual response of an organism to a chemical increases/decreases proportionally to the exposure. This gives rise to a monotonic dose-response relationship, when the effect either increases or decreases over the full dose range tested. The possibility exists that non monotonic dose-response relationship (NMDR) occurs, when the slope of the curve changes sign somewhere within the range of doses examined. The case of essential trace elements (ETE) with U-shaped or inverted Ushaped profile is well known. Non-linearities in toxicokinetics process may be the cause of NMDR, when the mechanism of action is strictly concentration dependent. NMRD can be also observed in studies where high-doses alter the experimental model, thus decreasing the observed response. This could occur when cytotoxic doses are tested in in vitro studies or in vivo, when using doses that are excessively toxic to animals (doses exceeding the maximum tolerable dose) can reduce the onset of an effect. The same could happen when the formation of aggregates, colloids or micelles at high concentrations reducing bioavailability and therefore toxicity evident at lower concentrations. It is likely that these phenomena could contribute to generate ‘apparent’ NMDR. The existence of a NMDR should be carefully evaluated, considering that: testing one dose level only is not sufficient to demonstrate a causal relationship; a wide dose range, statistical plausibility, and reasonably closely spaced dose intervals are necessary to demonstrate U-shaped dose-responses; data should be reproducible. http://dx.doi.org/10.1016/j.toxlet.2015.08.144
W12-4 Diapered skin and diaper dermatitis: Implications for risk assessment S. Felter Procter & Gamble, Central Product Safety, Mason, OH, United States Infant skin in the nappy area is recognized as having characteristics that potentially warrant special consideration in risk assessment. This is a result of the area being covered with a semiocclusive diaper which can lead to increased hydration of the skin. In addition, contact with urine and feces occurs frequently and can contribute to nappy dermatitis, which is most commonly seen in infants 6–12 months old. While modern diapers have led to a reduction in the frequency of nappy dermatitis, it is still a relatively common occurrence, although episodes of diaper rash are generally short-lived. Because diaper rash is associated with a disruption of skin barrier properties, it can result in greater penetration of chemicals through the skin, which must be considered in the safety assessment of any products used in the nappy area. The magnitude of this impact is expected to vary, depending on the extent and severity of the rash and the physical-chemical properties of the chemical in contact with the skin. For some chemicals, the impact will be negligible. For others, the impact might be greater but it will only be for a short period of time as the duration of diaper rash events is typically only a few days. This talk will provide an up-todate evaluation of the frequency, severity, and duration of diaper rash, and how this can impact overall exposure to chemicals with a range of physical–chemical characteristics. It is concluded that the overall impact is generally quite small and that current risk assessment methods are adequately protective, even when one considers the potential for occasional diaper rash. http://dx.doi.org/10.1016/j.toxlet.2015.08.142
W12-5 Quantitative Risk Assessment in the EU of Cosmetics for Babies and Children V. Rogiers Vrije Universiteit Brussel, In Vitro Toxicology and Dermato-Cosmetology, Brussels, Belgium The safety of cosmetics in the EU is regulated by Regulation 1223/2009 and is based on safe ingredients. It also applies for cosmetics of babies/children. Two channels are in place: (i) one functions under DG SANTE through the Scientific Committee on Consumer Safety (SCCS) and is concerned with Annex ingredients, composed of prohibited (II) and restricted substances (III), colorants (IV), preservatives (V) and UV-filters (VI); (ii) a second safety layer consists of risk assessment by the industry and concerns all finished products with their composing ingredients. In both channels, risk characterization of a substance is a combination of hazard identification, dose response and exposure assessment. Since March 2013, only animal-free validated methods may be applied. This creates a major challenge. Although for most endpoints of local toxicity and short-term exposure validated alternatives exist, this is not true for long-term tests e.g. repeated dose toxicity and developmental toxicity, carcinogenicity and toxicokinetics. The former tests are crucial as they usually deliver the No Observed Adverse Effect Level (NOAEL)-values, used in the calculation of the margin of safety (MoS = NOAEL/SED > 100, SED being the systemic exposure dose). 100 = 10×10 represents the inter-species × intra-species safety fac-
S51
tor. As “babies” are developing organisms, age is crucial and various stages of immaturity and maturation need to be considered at the anatomical and functional level. Also, clear definitions should be established. The intra-species factor of 10 is high enough in case of intact skin, but additional factors may be required for damaged skin as could occur in the nappy area (young babies, specific conditions of napkin dermatitis). Also infections need to be considered. Special concern has been expressed for adequate sun protection. 18 g/day, the exposure value used today in MoS-calculations, was found to be protective for babies/children. http://dx.doi.org/10.1016/j.toxlet.2015.08.143 Workshop W13: Non-Monotonic Dose–Response Curve in Hormonally Active Substances W13-1 Dose-response relationship: Monotone vs non-monotone curve E. Testai Istituto Superiore di Sanità, Environment and Primary Prevention, Rome, Italy Many chemicals are able to interfere with the complex endocrine network. Some interactions produce an homeostatic or adaptive response which cannot be considered adverse unless the so called “threshold of adversity” is exceeded. Endocrine disruptors (ED) acts with different mode of action which should be biological plausible; potency and causal relationship should also be taken into account. Regarding ED there is a strong debate about the ‘low dose hypothesis’, according to which low dose effects, not present at higher doses, may display a non-monotonic dose-response (NMDR). In the case of a NMDR curve the traditional NOAEL/BMDL point of departure cannot be used to derive a health-based guidance value. Indeed, the paradigm in risk assessment is that the individual response of an organism to a chemical increases/decreases proportionally to the exposure. This gives rise to a monotonic dose-response relationship, when the effect either increases or decreases over the full dose range tested. The possibility exists that non monotonic dose-response relationship (NMDR) occurs, when the slope of the curve changes sign somewhere within the range of doses examined. The case of essential trace elements (ETE) with U-shaped or inverted Ushaped profile is well known. Non-linearities in toxicokinetics process may be the cause of NMDR, when the mechanism of action is strictly concentration dependent. NMRD can be also observed in studies where high-doses alter the experimental model, thus decreasing the observed response. This could occur when cytotoxic doses are tested in in vitro studies or in vivo, when using doses that are excessively toxic to animals (doses exceeding the maximum tolerable dose) can reduce the onset of an effect. The same could happen when the formation of aggregates, colloids or micelles at high concentrations reducing bioavailability and therefore toxicity evident at lower concentrations. It is likely that these phenomena could contribute to generate ‘apparent’ NMDR. The existence of a NMDR should be carefully evaluated, considering that: testing one dose level only is not sufficient to demonstrate a causal relationship; a wide dose range, statistical plausibility, and reasonably closely spaced dose intervals are necessary to demonstrate U-shaped dose-responses; data should be reproducible. http://dx.doi.org/10.1016/j.toxlet.2015.08.144