Patch testing hydroperoxides of limonene and linalool in consecutive patients-Results of the IVDK 2018-2020.

BACKGROUND: Hydroperoxides of limonene (Lim-OOHs) and linalool (Lin-OOHs) are potent contact sensitizers. OBJECTIVES: To investigate the prevalence of positive patch test (PT) reactions to Lim-OOHs and Lin-OOHs in consecutive patients, their demographic factors and concomitant reactions. METHODS: Between 7/2018 and 12/2020, Lim-OOHs 0.3% pet. and Lin-OOHs 1% pet. were patch tested in 5511 consecutive patients. We assessed PT reactivity and analysed data from patients with either positive or negative PTs to Lim-OOHs and Lin-OOHs. RESULTS: Positive PT results to Lim-OOHs (n = 170, 3.1%) and Lin-OOHs (n = 483, 8.8%) were frequent. Most of the positive reactions were weak (LimOOHs n = 134/LinOOHs n = 429), and even more frequently, doubtful (n = 252/n = 578) or irritant reactions (n = 81/n = 178) were documented. PT reactivity to Lim-OOHs and Lin-OOHs was increased in patients with irritant reactions to sodium lauryl sulphate (SLS). The proportion of leg dermatitis and concomitant positive reactions to fragrances and essential oils was increased in patients with reactivity to these hydroperoxides. CONCLUSION: The observed reaction pattern suggests that both test preparations display an irritant potential with an increased risk of false positive reactions. Preparations should be chemically monitored in order to reduce irritancy. Mindful interpretation of PT results and aimed patch testing of lower concentrations is recommended.

A negative breakdown test in a fragrance mix I-positive patient does not rule out contact allergy to its fragrance constituents.

BACKGROUND: In about half of the patients reacting positive to fragrance mix I (FM I), breakdown testing remains negative. This raises the question of whether the reaction to FM I is false-positive, or the breakdown test is false-negative. OBJECTIVES: To identify characteristics and sensitization patterns of patients positive to FM I, but not to its fragrance constituents. PATIENTS AND METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK) between 2005 and 2019. Three patient groups were defined according to their reaction pattern: Group I, FM I positive and ≥1 single fragrance positive in the breakdown test (n = 1912); Group II, FM I positive and breakdown test negative (n = 1318); Group III, FM I negative (n = 19 790). RESULTS: Regarding the pattern of concomitant reactions to other fragrances, Group II had an intermediate position between Group I and Group III. In other respects (age and sex distribution, frequency of sensitization to non-fragrance baseline series allergens), Group II rather resembled Group I. CONCLUSIONS: Not every positive reaction to FM I in patients with negative breakdown tests is false-positive. There may be false-negative reactions to the single fragrance components when patch tested at 1% pet. Raising patch concentrations of some single fragrances is recommended.

The methylisothiazolinone epidemic goes along with changing patients' characteristics - After cosmetics, industrial applications are the focus.

BACKGROUND: Sensitization to methylisothiazolinone (MI) has seen an exceptional epidemic, mainly attributed to its use in cosmetics. OBJECTIVES: To trace the epidemic of MI allergy (2009-2018), and to analyze a possible change of patients' characteristics. METHODS: Informationsverbund Dermatologischer Kliniken-data of patients patch tested between 2009 and 2018 with MI (0.05% aq.) were analyzed concerning anamnestic items and sensitization frequencies. RESULTS: Overall, 4.9% reacted positive to MI. Comparing sensitization to MI in three periods (2009, 2013/14, and 2017/18), there was an increase to 7% in 2013 and a decrease to 3.4% in 2018. The MOAHLFA Index (M=Men, O=Occupational Dermatitis, A=Atopic Dermatitis, L=Leg Dermatitis, F=Face Dermatitis, A= Age > 40) for the period 2013/14 is characterized by a lower proportion of occupational dermatitis and a higher proportion of face dermatitis. The period 2017/18 is characterized by increases of occupational dermatitis and hand dermatitis, and a decrease of face dermatitis. Painters, personal care workers, and hairdressers were particularly affected. Sensitization in hairdressers and personal care workers (mostly cosmeticians) decreased after the peak in 2013/14, whereas sensitization to MI in painters continued to increase. CONCLUSIONS: After an unprecedented epidemic of MI allergy, mainly caused by its use in cosmetics, the continuous use of MI in industrial applications, for example, paints, and subsequent sensitization remain a matter of concern.

S3 guidelines: Epicutaneous patch testing with contact allergens and drugs - Short version, Part 1.

Epicutaneous patch testing is the diagnostic standard for the detection of allergic contact dermatitis. The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology and allergology as well as other medical specialties involved in establishing the indication for patch testing and its execution in patients with contact dermatitis and other forms of delayed-type hypersensitivity. The target audience also includes other health care providers and insurance funds. Based on a systematic literature search and a formal consensus process (S3), the guidelines were developed by dermatologists in collaboration with pediatricians, occupational medicine physicians, nursing staff as well as patient representatives. The systematic methodological approach and appraisal of evidence upon which the recommendations are based are outlined in a separate method report that also contains evidence tables. The guidelines address general aspects of patch testing as well as medicolegal issues. The recommendations given relate to topics such as the indication for patch testing, informed patient consent, as well as the choice of test substances, test chambers and test site, duration of exposure, reading times and interpretation of test reactions. Furthermore, recommendations are provided with respect to endogenous and exogenous factors, specific patient groups (children, pregnant women, immunosuppressed individuals) as well as possible risks and adverse events associated with patch testing using contact allergens. Note: This publication is part 1 of the short version of the S3 guidelines for "Epicutaneous patch testing using contact allergens and drugs" (registry no. 013 - 018; date: March 20, 2019; valid until December 31, 2021). Part 2 of the short version will be published in the next issue. The long version of these guidelines can be accessed at www.awmf.org. The method report is available as online publication (https://www.awmf.org/leitlinien/detail/ll/013-018.html) and contains the evidence tables in its appendix.

S3 Guidelines: Epicutaneous patch testing with contact allergens and drugs - Short version, Part 2.

Epicutaneous patch testing is the diagnostic standard for the detection of allergic contact dermatitis. The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology and allergology as well as other medical specialties involved in establishing the indication for patch testing and its execution in patients with contact dermatitis and other forms of delayed-type hypersensitivity. The target audience also includes other health care providers and insurance funds. Based on a systematic literature search and a formal consensus process (S3), the guidelines were developed by dermatologists in collaboration with pediatricians, occupational medicine physicians, nursing staff as well as patient representatives. The systematic methodological approach and appraisal of evidence upon which the recommendations are based are outlined in a separate method report that also contains evidence tables. The guidelines address general aspects of patch testing as well as medicolegal issues. The recommendations given relate to topics such as the indication for patch testing, informed patient consent, as well as the choice of test substances, test chambers and test site, duration of exposure, reading times and interpretation of test reactions. Furthermore, recommendations are provided with respect to endogenous and exogenous factors, specific patient groups (children, pregnant women, immunosuppressed individuals) as well as possible risks and adverse events associated with patch testing using contact allergens.

Skin sensitization quantitative risk assessment for occupational exposure of hairdressers to hair dye ingredients.

Occupational exposure of hairdressers to hair dyes has been associated with the development of allergic contact dermatitis (ACD) involving the hands. p-Phenylenediamine (PPD) and toluene-2,5-diamine (PTD) have been implicated as important occupational contact allergens. To conduct a quantitative risk assessment for the induction of contact sensitization to hair dyes in hairdressers, available data from hand rinsing studies following typical occupational exposure conditions to PPD, PTD and resorcinol were assessed. By accounting for wet work, uneven exposure and inter-individual variability for professionals, daily hand exposure concentrations were derived. Secondly, daily hand exposure was compared with the sensitization induction potency of the individual hair dye defined as the No Expected Sensitization Induction Levels (NESIL). For PPD and PTD hairdresser hand exposure levels were 2.7 and 5.9 fold below the individual NESIL. In contrast, hand exposure to resorcinol was 50 fold below the NESIL. Correspondingly, the risk assessment for PPD and PTD indicates that contact sensitization may occur, when skin protection and skin care are not rigorously applied. We conclude that awareness of health risks associated with occupational exposure to hair dyes, and of the importance of adequate protective measures, should be emphasized more fully during hairdresser education and training.

Factors associated with p-phenylenediamine sensitization: data from the Information Network of Departments of Dermatology, 2008-2013.

BACKGROUND: Risk factors for p-phenylenediamine (PPD) sensitization include the use of hair dyes, the application of temporary black henna tattoos, working as a hairdresser, and, possibly, exposure to hair dye pretests. OBJECTIVES: To quantify the impact of these (putative) risk factors on PPD sensitization. METHODS: Six items related to PPD exposure were added to the routine Information Network of Departments of Dermatology questionnaire from 2008 to 2013. A retrospective analysis of data from 4314 patients tested with PPD 1% pet. was conducted. RESULTS: Of the PPD-positive patients (n = 271), 80% had their hair dyed, and, of these, 57% subsequently developed scalp dermatitis, whereas only 11% had had a henna tattoo. The self-administrated pretest with hair dye was performed by only a few patients, precluding a more detailed analysis. Hair dyeing [odds ratio (OR) 6.0; 95% confidence interval (CI): 3.9-9.4], henna tattoos (OR 2.4; 95%CI: 1.5-3.7) and being a hairdresser (OR 2.1; 95%CI: 1.3-3.2) increased the risk of PPD sensitization. Neither dyeing of own hair nor application of a temporary henna tattoo seemed to affect PPD sensitization in hairdressers. p-Aminoaryl compounds more often gave positive reactions in patients with henna tattoo. CONCLUSIONS: Hair dyeing is the major risk factor for PPD sensitization in this clinical setting, and application of a temporary black henna tattoo may also lead to (strong) PPD sensitization.

European Surveillance System on Contact Allergies (ESSCA): polysensitization, 2009-2014.

BACKGROUND: Polysensitization, defined as being allergic to three or more haptens from the European baseline series, is considered to reflect increased susceptibility to developing a contact allergy, and is likely to be associated with an impaired quality of life. OBJECTIVES: To evaluate the prevalences of polysensitization across Europe and to analyse factors associated with polysensitization. METHODS: Patch test data collected by the European Surveillance System on Contact Allergies (ESSCA; www.essca-dc.org) in consecutively patch tested patients from January 2009 to December 2014, comprising 11 countries and 57 departments, were retrospectively analysed. RESULTS: A total of 86 416 patients were available for analysis, showing a standardized prevalence of polysensitization of 7.02%, ranging from 12.7% (Austria) to 4.6% (Italy). Allergen pairs with the strongest association are reported for the total population, for South Europe, and for North/Central Europe. Overall, polysensitized patients showed a higher percentage of extreme (+++) positive patch test reactions than oligosensitized patients. Female sex, occupational dermatitis and age > 40 years were risk factors for polysensitization. CONCLUSIONS: The varying prevalences of polysensitization across Europe most likely reflect differences in patient characteristics and referral patterns between departments. Known risk factors for polysensitization are confirmed in a European dermatitis population.

Differences in contents of organochlorine impurities do not influence responses to patch testing with Majantol®.

BACKGROUND: Majantol® [2,2-dimethyl-3-(3-methylphenyl)propan-1-ol; CAS no. 103694-68-4] has been identified as a contact allergen in humans, despite negative animal tests. Hence impurities, specifically organochlorines, in Majantol® might have been the reason for positive patch test reactions in the past. OBJECTIVES: To assess elicitation via patch testing with a standard market-quality version of Majantol® ('normal') with a normal content of organochlorine impurities, as compared with an ultra-purified version of Majantol® ('pure'), without detectable organochlorine impurities. METHODS: Between 1 October 2013 and 31 December 2014, two different Majantol® patch test preparations of the above-mentioned quality were tested 5% pet. in parallel in the 'monitor series', that is, together with the baseline series, in 8005 consecutive patients from 33 departments of dermatology of the Information Network of Departments of Dermatology (IVDK). RESULTS: Fifty-three of 7740 [0.69% (95%CI: 0.51-0.87)] patch tested patients reacted to at least one Majantol® preparation. The majority (n = 32) (60.4%) reacted to both preparations, 13 (24.5%) reacted to the 'normal' version only, and 8 (15.1%) reacted to the 'pure' version only. There was good concordance between results [Cohen's kappa 0.75 (95%CI: 0.65-0.85)], and there was no significant difference in frequency or intensity between the two preparations. More doubtful or irritant reactions than positive reactions were observed, and> 80% of all positive reactions were weak positive. CONCLUSION: Organochlorine impurities are very probably not the cause of allergic reactions to Majantol®.

Contact allergy to ingredients of topical medications: results of the European Surveillance System on Contact Allergies (ESSCA), 2009-2012.

PURPOSE: The aim of this study was to give an overview of the prevalence of contact allergy to active ingredients and excipients of topical medications across Europe. METHODS: Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (www.essca-dc.org) with substances applied to consecutively patch tested patients, 2009-2012, in 54 departments in 12 European countries. RESULTS: In view of the varying composition of the baseline series used in the previously mentioned departments and countries, between 58 833 (lanolin alcohols) and 16 498 patients (sodium metabisulfite) were patch tested with the topical agents covered in this study. Among these, positive (allergic) reactions were most commonly observed to sodium metabisulfite (3.12% positive), followed by propolis (2.48%), Compositae mix (1.73%), lanolin alcohols (1.65%) and caine mix III (benzocaine, cinchocaine and tetracaine; 1.27%). CONCLUSIONS: Several of the substances warrant routine screening for contact allergy, i.e. patch testing in a baseline series. However, in view of a vast number of other topical agents, additional patch testing with the suspect topical drug preparations (including natural remedies and cosmetics) is warranted. In the event of a positive test to the (pharmaceutical) product, single ingredients should be tested individually to precisely identify the hapten(s). Copyright © 2016 John Wiley & Sons, Ltd.

A variant of the CXCL11 gene may influence susceptibility to contact allergy, particularly in polysensitized patients.

BACKGROUND: Hereditary factors may influence individual susceptibility to contact allergy. OBJECTIVES: To investigate genetic variants with impacts on early inflammatory reactions and T cell functions that possibly increase the risk of contact allergy. PATIENTS AND METHODS: Three hundred and seventy two patients undergoing patch testing were recruited from the Information Network of Departments of Dermatology (IVDK). Of these, 133 were monosensitized and 239 were polysensitized, defined as reacting to three or more unrelated sensitizers. Within the polysensitized individuals, a subgroup with at least one particularly strong patch test reaction (strong reactors; n = 194) was considered. Three hundred and forty-seven blood bank donors served as controls. Fifteen genetic variants in 13 genes were analysed. RESULTS: The homozygous variant CXCL11 AA genotype (rs6817952) was significantly more frequent among polysensitized patients (10 of 239 = 4.2%; p = 0.0048; odds ratio 7.49; 95%CI: 1.7-36.1) than among monosensitized patients (2.2%) and in the control group (0.6%). None of the remaining genetic variants investigated were characterized by similarly strong associations. However, the significance was lost after correction for multiple comparisons. CONCLUSIONS: The homozygous variant CXCL11 genotype is associated with an increased risk of contact allergy. To confirm this exploratory finding, further independent studies are needed.

Patch test results in children and adolescents across Europe. Analysis of the ESSCA Network 2002-2010.

BACKGROUND: Contact sensitization in children is more frequent than previously thought. METHODS: The ESSCA collected patch test data from 11 European countries aggregated to 4 European regions. RESULTS: Six thousand and eight patients aged 1-16 years old with suspected allergic contact dermatitis were analyzed during a period of 8 years (2002-2010). The overall prevalence of at least one positive reaction to a hapten was 36.9%. The 10 most frequent haptens were as follows: nickel sulfate, cobalt chloride and potassium dichromate, neomycin sulfate, Myroxylon pereirae resin (balsam of Peru), para-phenylenediamine, chloromethylisothiazolinone/methylisothiazolinone 3:1, fragrance mix, lanolin alcohols, and colophony. No difference was found in the prevalence of at least one positive reaction to at least one hapten between boys and girls and between children with atopic dermatitis and children without. Children without atopic dermatitis, when compared with those with, had a significantly higher prevalence of contact sensitization for nickel sulfate (20.91% vs 16.87%, respectively), 4-tert. butylphenol formaldehyde resin (1.61% vs. 0.7%), and para-phenylenediamine (2.49% vs. 1.3%). LIMITATIONS OF THE STUDY: Chamber loading is not an exact science and variation may occur between staff and departments. Interinstitution variations in readings can occur. A possible geographic confounder is that the southern regions tested more children in the younger age group. Relevance was not addressed due to difficulties in the application of a set of uniform definitions. CONCLUSIONS: Our study adds information on the most common contact allergens detected in children which could help to define a Standard European Pediatric Baseline Series.

Reactivity to sorbitan sesquioleate affects reactivity to fragrance mix I.

BACKGROUND: Fragrance mix I (FM I) and its single constituents contain 5% and 1% sorbitan sesquioleate (SSO), respectively. SSO is a rare sensitizer and a potential irritant. OBJECTIVES: To determine whether the outcome of the FM I breakdown test is affected by positive patch test reactivity to SSO. METHODS: A retrospective analysis of data from the Information Network of Departments of Dermatology, 1998-2013, was performed. RESULTS: The full FM I breakdown test including SSO was tested in 2952 patients. Of these, 154 (5.2%) had a positive patch test reaction to SSO 20% pet. and 2709 (91.8%) had a negative patch test reaction. Positive reactions to one or more of the single fragrances contained in the mix were significantly more common (82.5% versus 57.3%) in SSO-positive patients, who also had more multiple reactions than FM I-positive patients with negative SSO reactions (61.5% versus 21.3% patients with reactions to two or more fragrances). CONCLUSIONS: Our results indicate that reactivity to SSO markedly affects the outcome of patch testing with FM I and its single constituents. SSO must be an obligatory part of the full FM I breakdown test, and should ideally be included in the baseline series.

Occupational contact allergy in nurses: results from the Information Network of Departments of Dermatology 2003-2012.

BACKGROUND: Healthcare workers are occupationally exposed to various allergens in protective gloves, surface or instrument disinfectants, drugs, and skin care products. An increased prevalence of sensitization to thiurams, glutaraldehyde, formaldehyde and glyoxal in nurses with occupational contact dermatitis (OCD) has been known since the 1990s. OBJECTIVES: To update the range of occupational allergens in healthcare professionals. METHODS: We retrospectively analysed patch test data from the Information Network of Departments of Dermatology (IVDK), 2003-2012. Patch test results from 2248 nurses with OCD were compared with those of 2138 nurses without OCD. RESULTS: Significantly increased sensitization rates were found for thiuram mix (6.7%), potassium dichromate (5.7%), methylchloroisothiazolinone/methylisothiazolinone (4.4%), colophonium (3.4%), 2-bromo-2-nitropropane-1,3-diol (1.7%), and zinc diethyldithiocarbamate (1.7%). Patch testing with products from the patients' workplaces gave additional clues to further allergens, for example tetrazepam. CONCLUSIONS: The known range of contact sensitization in nurses with OCD has been confirmed. Formaldehyde allergy seems to be less important today. Drugs such as tetrazepam are occupational sensitizers in nurses. The increase in chromium sensitization remains unexplained.

Genetic factors in susceptibility to contact sensitivity.

There are clear differences in individual susceptibility to the development of contact allergies; some individuals readily become allergic to many chemicals, and others remain clinically tolerant of everything that they come into contact with. A great number of molecules and pathways can contribute to the perturbation by xenobiotics and the subsequent possible immune response. It is necessary to consider susceptibility in two ways: as allergen-specific and as non-allergen-specific. It is likely that different receptor pathways and processes will be involved in the different forms of susceptibility. As investigations of the genetic control of such susceptibility have failed to identify major genetic control, it is likely that small contributions will be made by many components. Whereas genome-wide associations and transcriptome analyses may reveal genetic clues in the future, explanation of how/why the expression of multiple molecular components can be controlled in a coordinated fashion may follow from investigation of microRNAs. It is becoming clear that microRNAs can regulate the expression of multiple genes and even multiple components of biochemical pathways.

Patch test results of the European baseline series among patients with occupational contact dermatitis across Europe - analyses of the European Surveillance System on Contact Allergy network, 2002-2010.

BACKGROUND: Occupational contact dermatitis is one of the most common occupational diseases in Europe. In order to develop effective preventive measures, detailed and up-to-date data on the incidence, main causes and professions at risk of occupational contact dermatitis are needed. OBJECTIVES: To describe the pattern of patch test reactivity to allergens in the European baseline series of patients with occupational contact dermatitis in different occupations. METHODS: We analysed data collected by the European Surveillance System on Contact Allergy (ESSCA) network from 2002 to 2010, from 11 European countries. RESULTS: Allergens in the European baseline series associated with an at least doubled risk of occupational contact dermatitis include: thiuram rubber chemical accelerators, epoxy resin, and the antimicrobials methylchloroisothiazolinone/methylisothiazolinone, methyldibromo glutaronitrile, and formaldehyde. The highest risk of occupational contact dermatitis was found in occupations classified as 'other personal services workers', which includes hairdressers, nursing and other healthcare professionals, precision workers in metal and related materials, and blacksmiths, tool-makers and related trades workers. CONCLUSIONS: In the planning and implementation of measures aimed at preventing occupational contact dermatitis, the focus should be on the identified high-risk occupational groups and the most common occupational allergies.

ESSCA results with the baseline series, 2009-2012: rubber allergens.

BACKGROUND: Allergic contact dermatitis caused by rubber allergens is common, and causes significant patient morbidity. Contemporary data are important to allow appropriate preventive measures and identification of contact allergy trends. OBJECTIVES: To describe the pattern of patch test reactivity to rubber allergens, including those in the European baseline series. METHODS: Data collected by the European Surveillance System on Contact Allergies (ESSCA) network between 2009 and 2012 from 12 European countries were analysed. RESULTS: Contact allergy to thiuram mix declined over the studied time period, with an overall prevalence of 1.87%. The prevalence of allergy to carba mix was 2.29%, and was significantly increasing. Prevalence rates of sensitization to other rubber allergens were largely unchanged. Statistical analysis with the MOAHLFA index confirmed the strong links between rubber allergy and occupational hand dermatitis. CONCLUSIONS: Changing patterns of allergy to rubber additives have been identified. Inclusion of carba mix in the European baseline series may be appropriate.

DKG statement on the use of metal alloy discs for patch testing in suspected intolerance to metal implants.

Intolerance reactions to metal implants may be caused by metal allergy. However, prior to implantation, 'prophetic'/prophylactic patch testing should not be performed. Pre-implant patch testing should only be done to verify or exclude metal allergy in patients with a corresponding history. In case of implant-related complications - in particular following replacement arthroplasty - such as pain, effusion, skin lesions, reduced range of motion or implant loosening, orthopedic causes should be ruled out first. Workup of suspected metal implant allergy should then be done using the DKG standard series, which includes nickel, cobalt, and chromium preparations. Various studies assessing the usefulness of metal alloy discs for patch testing have shown this particular approach to be ineffective with respect to providing reliable information on metal allergy. Any positive reaction in such tests cannot be assigned to a specific metal contained within the alloy. Furthermore, there is a risk of broad and indiscriminate use of these readily available discs. Accordingly, given the lack of additional benefit compared to patch testing with standardized metal salt preparations, we do not recommend patch testing with metal alloy discs.

Contact sensitization to cobalt--multifactorial analysis of risk factors based on long-term data of the Information Network of Departments of Dermatology.

BACKGROUND: Cobalt contact sensitization in consecutively tested patients is common. The sources of exposure, and thus clinical relevance, are mostly unclear. OBJECTIVE: To examine (i) long-term time trends of sensitization, (ii) risk factors that may point to relevant exposures, and (iii) coupling with nickel sensitization. METHODS: Data of all patients patch tested with cobalt(II) chloride hexahydrate (1% pet.) between 1992 and 2012 (n = 185 050) in the Information Network of Departments of Dermatology (IVDK, www.ivkd.org) were subjected to descriptive stratified and Poisson regression analysis. RESULTS: The overall prevalence of positive patch test reactions was 5.23% (95% confidence interal 5.13-5.33%). Regarding time trends, there were significant increases for males aged 18-44 years and for females aged ≥45 years, and a significant variation of co-reactivity with nickel over time. Female sex almost doubled the risk of sensitization; age ≥45 years was associated with a 30% decrease in the risk of positive patch test reactions to cobalt, and atopic eczema with an approximately 20% increase. CONCLUSIONS: Notwithstanding some diagnostic difficulties with the test preparation, a persistent, notable proportion of cobalt sensitization, isolated or coupled with nickel allergy, can be observed. This warrants further in-depth research into causative exposures, both at the workplace and in consumers.