Triggering factors in sensitive skin from the worldwide patients' point of view: a systematic literature review and meta-analysis.

Sensitive skin (SS) is a syndrome defined by the occurrence of unpleasant sensations in response to stimuli that normally should not provoke such sensations. In most patients, symptoms occur within 1 h following exposure to trigger factors and may persist for minutes or even hours. Numerous triggering factors (physical, chemical or psychological) are suspected and described in articles. The aim of this article was to perform a systematic literature review to collect data on the triggering factors involved in SS and to then perform a meta-analysis. Thirteen studies were included in the systematic literature review. Subjects were classified into groups, SS or no sensitive skin (NSS), and triggering factors were researched through responses to different questions. SS could be triggered by numerous factors. The most important triggering factor was cosmetics, with an odds ratio (OR) equal to 7.12 [3.98-12.72]. Other triggering factors were physical (variations in temperature, cold, heat, wind, sun, air conditioning, wet air and dry air), chemical (water and pollution) or psychological (emotional) factors. After cosmetics, the most important factors were wet air, OR 3.83 [2.48-5.91]; air conditioning, OR 3.60 [2.11-6.14]; heat, OR 3.5 [2.69-4.63]; and water, OR 3.46 [2.56-4.77].

Qualitative and quantitative composition of essential oils: A literature-based database on contact allergens used for safety assessment.

The risks related to the use of essential oils are difficult to ascertain at present, due in part to the large number of different oils available on the market, making it difficult for the risk assessor. Essential oils may contain skin allergens in significant amounts, and could thus pose a risk to the consumer. The aim of our study was to collect as much qualitative and quantitative data as possible on allergens present in essential oils. 11 types of essential oils, with 25 respective subspecies, were taken into account based on a previous survey. Based on the literature, 517 dosages were recorded from 112 publications, providing precious information for probabilistic exposure assessment purposes. 22 substances recognized as established allergens were found in the essential oils we included. Of these, 11 are also found in cosmetics as fragrance components. These results are of major importance regarding co-exposure to fragrance allergens. Moreover, this could lead to regulatory measures for essential oils in the future, as it is the case for cosmetic products, in order to better protect consumers against skin allergy.

Usage patterns of aromatherapy among the French general population: A descriptive study focusing on dermal exposure.

Although likely benefits of aromatherapy are well documented, little is known about essential oils consumption and exposure to molecules present in the oils. The aim of our study was to determine usage patterns of 12 types of essential oils among a quite large panel, sorted per sex and quintile of age from birth to 70. A survey was conducted in September 2014 among 1507 French individuals, selected to build a representative panel of the general population. The key point of our study, apart from the fact that it has never been done among general population, was the focus on dermal exposure. Information about types of essential oils used, skin areas exposed, frequencies and quantities were collected. Our work revealed that some sub-populations could be significantly exposed to molecules of toxicological concern, especially in terms of skin sensitization. This work is the first step to assess human exposure to these molecules, and will help safety authorities and risk managers to protect the population.

Human variability in influx and efflux transporters in relation to uncertainty factors for chemical risk assessment.

Transporters are divided into the ABC and SLC super-families, mediating the cellular efflux and influx of various xenobiotic and endogenous substrates. Here, an extensive literature search was performed to identify in vivo probe substrates for P-gp, BCRP and OAT1/3. For other transporters (e.g. OCT, OATP), no in vivo probe substrates could be identified from the available literature. Human kinetic data (Cmax, clearance, AUC) were extracted from 142 publications and Bayesian meta-analyses were performed using a hierarchical model to derive variability distributions and related uncertainty factors (UFs). For P-gp, human variability indicated that the kinetic default UF (3.16) would cover over 97.5% of healthy individuals, when considering the median value, while the upper confidence interval is exceeded. For BCRP and OAT1/3 human variability indicated that the default kinetic UF would not be exceeded while considering the upper confidence interval. Although limited kinetic data on transporter polymorphisms were available, inter-phenotypic variability for probe substrates was reported, which may indicate that the current default kinetic UF may be insufficient to cover such polymorphisms. Overall, it is recommended to investigate human genetic polymorphisms across geographical ancestry since they provide more robust surrogate measures of genetic differences compared to geographical ancestry alone. This analysis is based on pharmaceutical probe substrates which are often eliminated relatively fast from the human body. The transport of environmental contaminants and food-relevant chemicals should be investigated to broaden the chemical space of this analysis and assess the likelihood of potential interactions with transporters at environmental concentrations.

Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment.

Human variability in paraoxonase-1 (PON1) activities is driven by genetic polymorphisms that affect the internal dose of active oxons of organophosphorus (OP) insecticides. Here, an extensive literature search has been performed to collect human genotypic frequencies (i.e. L55M, Q192R, and C-108T) in subgroups from a range of geographical ancestry and PON1 activities in three probe substrates (paraoxon, diazoxon and phenyl acetate). Bayesian meta-analyses were performed to estimate variability distributions for PON1 activities and PON1-related uncertainty factors (UFs), while integrating quantifiable sources of inter-study, inter-phenotypic and inter-individual differences. Inter-phenotypic differences were quantified using the population with high PON1 activity as the reference group. Results from the meta-analyses provided PON1 variability distributions and these can be implemented in generic physiologically based kinetic models to develop quantitative in vitro in vivo extrapolation models. PON1-related UFs in the Caucasian population were above the default toxicokinetic UF of 3.16 for two specific genotypes namely -108CC using diazoxon as probe substrate and, -108CT, -108TT, 55MM and 192QQ using paraoxon as probe substrate. However, integration of PON1 genotypic frequencies and activity distributions showed that all UFs were within the default toxicokinetic UF. Quantitative inter-individual differences in PON1 activity are important for chemical risk assessment particularly with regards to the potential sensitivity to organophosphates' toxicity.

Risk assessment of exposure to mycotoxins (aflatoxins and fumonisins) through corn tortilla intake in Veracruz City (Mexico).

This study aimed to assess aflatoxin and fumonisin intake through corn tortilla consumption in Veracruz city. Between October 2013 and February 2015, a total of 120 corn tortilla samples (2 kg samples, 40 samples per year) were randomly collected. Aflatoxins and fumonisins were quantified by high performance liquid chromatography coupled with a fluorescence detector. A probability density function (PDF) was used for describing corn tortilla intake, body weight of the Veracruz city population, mycotoxin content of corn tortilla samples and estimated mycotoxin daily intake. The Monte Carlo method with 10,000 iterations was employed to assess the population exposure risk. The highest level of total aflatoxins (AFT) was 22.17 µg kg-1, and 526.6 µg kg-1 for fumonisins B1 plus B2, with 85% and 90% of contaminated samples respectively. Up to 69.7 % of the population was estimated to consume a higher aflatoxin dose than that recommended by the JECFA (1 ng kg-1 of body weight per day); it was found that the recommended dose was exceeded to a greater extent in the male population, due to higher consumption of corn. The risk of fumonisin intake was less than 5 % due to the low presence and levels of these toxins in corn tortillas. The results suggest that corn tortilla consumers are at dietary risk caused by AFT contamination; this information should be considered when taking action to protect public health.

Aggregate exposure to common fragrance compounds: Comparison of the contribution of essential oils and cosmetics using probabilistic methods and the example of limonene.

The knowledge of aggregate exposure to different types of products is paramount in the risk assessment. The aim of this study was to compare the relative contribution of essential oils compared to cosmetics on the daily dermal exposure to limonene, an ubiquitous fragrance compound that can be an allergen depending on its degree of oxidation. Aggregate daily exposure to limonene was calculated among a panel of French volunteers using both essential oils and cosmetics, for 4 different specific zones, i.e. face and neck, chest, upper limbs and lower limbs. Calculations were made using a probabilistic Monte Carlo method and sensitivity analysis. The main strength of this work was the inclusion of essential oils in addition to cosmetics in the model. For the first time, the generated data could be used to compare the contribution of these two products in dermal exposure. Essential oils appear to be significant contributors to exposure to limonene particularly for the face. This work is a first step that will permit to determine the exposure to other fragrance compounds with sensitizing potential. These data will be useful for risk managers to consider the inclusion of essential oils in the overall burden of this pathology.

Consumption of cosmetic products by the French population. Third part: Product exposure amount.

A recent study in France provided valuable data on the frequency and amount of use of cosmetic products (Ficheux et al., 2015, 2016a). The aim of the present study was to generate Product Exposure Amount data, i.e. the amounts of cosmetics applied to the skin among the French population using the raw data collected during the previous enquiry. These data are useful to derive Consumer exposure level data which are paramount for skin sensitization risk assessments. Exposure data were generated for 69 different cosmetics, classified as products for the hair, face, buccal hygiene, hands, feet, body, shaving and depilation, sunscreens as well as products specifically intended for babies. Exposure was calculated using a probabilistic Monte Carlo method. The main strength of this work was the break-down of data by age and sex. The results showed that some data used by the International Fragrance Association in skin sensitization risk assessments, in particular facial care products and deodorants, could be unsuitable for the protection of French consumers. For the first time, data were also generated for products intended for babies' nappy area. These data will be useful for the implementation of the Quantitative Risk Assessment for skin sensitization among the French population.

Adequacy of the default values for skin surface area used for risk assessment and French anthropometric data by a probabilistic approach.

The notes of guidance for the testing of cosmetic ingredients and their safety evaluation by the Scientific Committee on Consumer Safety (SCCS) is a document dedicated to ensuring the safety of European consumers. This contains useful data for risk assessment such as default values for Skin Surface Area (SSA). A more in-depth study of anthropometric data across Europe reveals considerable variations. The default SSA value was derived from a study on the Dutch population, which is known to be one of the tallest nations in the World. This value could be inadequate for shorter populations of Europe. Data were collected in a survey on cosmetic consumption in France. Probabilistic treatment of these data and analysis of the case of methylisothiazolinone, a sensitizer recently evaluated by a deterministic approach submitted to SCCS, suggest that the default value for SSA used in the quantitative risk assessment might not be relevant for a significant share of the French female population. Others female populations of Southern Europe may also be excluded. This is of importance given that some studies show an increasing risk of developping skin sensitization among women. The disparities in anthropometric data across Europe should be taken into consideration.

Probabilistic exposure assessment of sun care products.

The aim of this study has been to assess the consumption and the exposure to 6 types of sun care products: sunscreen cream, sunscreen milk, sunscreen spray, sunscreen stick, moisturizing cream with SPF and after-sun milk. Consumption data were obtained from 75 clinical safety studies conducted on 3001 subjects: 371 children aged 3-9, 149 children aged 10-14 and 2481 adults aged more than 15. Exposure was assessed using a probabilistic method. Strength of the study include stratification of consumption and exposure data according to sex and age, as well as other important points such as the galenic form, the site of application and the value of the sun protection factor.

Exposure assessment of family cosmetic products dedicated to babies, children and adults.

Very few consumption and exposure data is available for family cosmetic products. The aim of the present study was to assess the consumption and the exposure to family cosmetic products used by babies, children and adults. 10 categories of products were studied: shampoo, shower gel, solid soap, cleansing lotion, emollient foam, emollient bath, cream, milk, balm and lip balm. Consumption data were obtained from 2994 participants (789 babies aged 0-3 years, 837 children aged 4-12 years and 1368 adults aged more than 18 years) included in 87 clinical safety studies. Exposure was performed using a probabilistic method. The implementation of consumption and exposure assessment by age has strengthened this work, as consumption and mainly exposure differences were shown. In fact, babies were always the most exposed to family products, followed by children and adults. These original data will be useful for safety assessors and safety agencies in order to protect consumers.

Influence of the container on the consumption of cosmetic products.

The container, also known as primary package or inner package, could be defined as the packaging designed to come into direct contact with the cosmetic product. To author's knowledge, no study was available regarding the effect of the primary package on the consumption of cosmetic products. The aim of the study was to assess the impact of the container on the consumption of three cosmetic products widely used, i.e. shampoo, shower gel and emollient cream. The three products were contained in a tube with a flip top cap and in a bottle with a pump. The study was conducted on 221 French adults: 108 women and 113 men. Results showed that the consumption of each cosmetic product was slightly higher when the product was packaged in tube with a flip top cap than in bottle with a pump. The difference of consumption could vary from 5 % to 23 % when calculated with mean values. This information could be interesting for safety evaluators, safety agencies and commercial services of cosmetic manufacturers.

Statistical analysis of corn consumption for improved mycotoxin exposure estimates for the population of Veracruz City, Mexico.

Corn consumption was evaluated in the population of Veracruz City, Mexico, through two different dietary intake questionnaires. The selection of 300 sampling locations was completely random. The population was segregated into gender and age categories. A daily consumption questionnaire was used to determine the consumption of corn tortillas and a frequency questionnaire to determine the consumption of other corn products. A book of photographs was used to adjust criteria on the size of the portions of corn products and a probability distribution was built of the weight and content of corn for tortillas. Probability density functions (PDFs) were used to describe the consumption of each corn product. Men and those between 14 and 65 years old have the highest consumption of tortillas. Tortillas, antojitos, tacos and chilaquiles are the products that provide the largest amount of corn to the Veracruz people's diet. Even though these products are nixtamalisated, there is evidence that after a thermo-alkaline process some contaminants such as mycotoxins (like aflatoxin, which is a mutagenic, teratogenic and carcinogenic toxin) could be present in high concentrations. These results highlight the need to characterise the consumption of one of the main foods included in dietary staple in Mexico as a first step for a probabilistic risk assessment.

Probabilistic assessment of exposure to cosmetic products by French children aged 0-3 years.

Very few exposure data are available for children in Europe and worldwide. The aim of this study was to assess the exposure to cosmetic products used on children aged 0-3 years using recent consumption data generated for the French population. Exposure was assessed using a probabilistic method for 24 products including cleanser, skin care, fragrance, solar and bottom products. The exposure data obtained in this study for children aged 0-3 years were higher than the values fixed by the SCCS for all common products: liquid shampoo, face moisturizer cream, toothpaste, shower gel and body moisturizer cream. Exposure was assessed for the first time for many products such as sunscreens, Eau de toilette and massage products. These new French exposure values will be useful for safety assessors and for safety agencies.

Probabilistic assessment of exposure to hair cosmetic products by the French population.

Cosmetic exposure data are limited in Europe and especially in France. The aim of this study was to assess the exposure to hair cosmetics using recent consumption data (percentage of users, frequency of use and amount per use) generated for the French population (Ficheux et al., 2015, 2016). Exposure was assessed using a probabilistic method for eleven hair products: liquid shampoo, dry shampoo, conditioner, hair mask, hair serum, hair oil, styling lacquer, styling gel, styling foam, styling wax and styling spray. Exposure was assessed by sex and by age classes in adults and children. Pregnant women were also studied. For liquid shampoo, conditioner and some styling products (gel, lacquer and foam), the levels of exposure were higher than the values currently used by the Scientific Committee on Consumer Safety (SCCS). Exposure values found for styling wax and styling spray were lower than SCCS values. Exposure was assessed for the first time for dry shampoo, hair mask, hair serum and hair oil products. These new French exposure values will be useful for safety assessors and for safety agencies in order to protect the general population and these at-risk populations.

Exposure of hairdressers to the main cosmetics used in hairdressing salons in France: A preliminary study.

In recent years, more attention has been given to chemical exposure in hairdressers. This increasing interest is largely due to the various respiratory and skin symptoms observed in hairdressers. According to these symptoms, hairdressers are in contact with various sources of exposure. Particularly in France, little information is available to assess professional exposure of hairdressers. In order to gather information to assess exposure in hairdressers, 11 hairdressing salons were visited. All the salons were located in Brest City (France). Preferentially, small hairdressing salons were visited. Observations were performed to obtain salon characteristics and to record workers' practices. Calculations revealed that in the worst-case scenario, dermal professional exposure reaches 14.68 and 13.67 mg/kg/day for hair coloring and highlighting mixtures, respectively. Inhalation exposure represents 14.2 and 18.1 mg/kg/day for hair coloring and highlighting mixtures, respectively. These exposure values represent baseline values for exposure of French hairdressers working in small hairdressing salons.

Consumption of hair dye products by the French women population: Usage pattern and exposure assessment.

Only few published data are available in the literature about consumption and exposure, for hair dye products. The aim of this study was to assess the use of 10 different hair dye products in French Women with a focus on consumption of hair dye in different places of use (at home and at the hairdressers) in order to assess the corresponding dermal exposures. The assessment was performed on a total of 4237 women older than 15 years old, thanks to three national web surveys. The percentage of hair dye users among the French women population was about 64%.The mean frequency of use ranged between 2.23 and 14.22 times per year depending on the studied product and age category of women. This study provided the first data available for exposure to hair dye products with mean exposures ranging between 1.48 and 6.49 mg/kg bw/day depending on the product studied and age category of women. Moreover, consumption data obtained in this study might be useful to perform safety assessment of hair dye products thanks to the knowledge of the age categories of the population having the highest percentage of users and/or frequency of use.

Consumption of cosmetic products by the French population second part: Amount data.

The aim of the study was to assess the amount per use of cosmetic products consumed at home by the adult, child and baby French population. 1078 men and women participated in the study which was performed in four cities of France. This enquiry was performed on 106 cosmetics including general hygiene, skin care, hair care, hair styling, make-up, fragrances, solar, shaving and depilatory, and baby products. Coupled to frequency data previously obtained (Ficheux et al., 2015), these amounts per use data will be used in order to assess the exposure to cosmetics by the French population. These current exposure values could be useful for safety assessors and for safety agencies.

Digital image analysis of haematopoietic clusters.

Counting and differentiating cell clusters is a tedious task when performed with a light microscope. Moreover, biased counts and interpretation are difficult to avoid because of the difficulties to evaluate the limits between different types of clusters. Presented here, is a computer-based application able to solve these problems. The image analysis system is entirely automatic, from the stage screening, to the statistical analysis of the results of each experimental plate. Good correlations are found with measurements made by a specialised technician.

Consumption of cosmetic products by the French population. First part: frequency data.

The aim of this study was to assess the percentage of users, the frequency of use and the number of cosmetic products consumed at home by the French population. The evaluation was performed for adult, child and baby consumers. Pregnant women were also taken into account in this work. All in all, 141 products cosmetics including general hygiene, skin care, hair care, hair styling, make-up, fragrances, solar, shaving and depilatory products were studied. The strengths of the study were the separation of data by sex and by age groups, the consideration of a priori at risk subpopulations and the consideration of a large number of cosmetic products. These current consumption data could be useful for safety assessors and for safety agencies in order to protect the general population and these at risk subpopulations.