Background factors of chemical intolerance and parent–child relationships

Between 8 and 33% of people in various populations consider themselves to be unusually sensitive to odorous and pungent chemicals, with the variability in prevalence depending largely on a wide variety of definitions and severity. This condition, known as chemical intolerance (CI), is a frequently reported problem in industrialized countries [1‐9]. Multiple chemical sensitivity (MCS) and idiopathic environmental intolerance (IEI) are labels often used for severe cases of CI.

CI is a chronic acquired disorder characterized by non-specific and recurrent symptoms in multiple organ systems associated with exposure to low levels of odorous chemicals such as organic solvents, pesticides, perfumes, cleaning products, perfumes, tobacco smoke, car exhaust, or combustion products [10‐12]. Despite its relatively high prevalence in nonclinical samples, the diagnosis and etiology of CI remain controversial and understudied. Although the mechanisms behind CI are unknown, various theories highlight that alterations in chemical sensory transduction and neural processing, rather than toxic processes, serve as key components [13‐18].

Phenomenologically, the development of CI appears to be associated with a loss of tolerance following acute or chronic exposure to various environmental agents in daily life and the subsequent triggering of symptoms by extremely small quantities of previously tolerated chemicals [19]. Although the effect of age on CI is unclear, the prevalence of CI in persons ≥ 60 years of age is lower than that in other age groups [2, 4] and the prevalence of CI in teenagers is much lower than that in adults [20]. In addition, the importance of genetic factors involved in xenobiotic metabolism in CI etiology is still uncertain concerning the importance of genetic variability as opposed to epigenetic mutation [16, 21]. Although the underlying mechanisms between asthma/allergy and CI may be different, several studies reported comorbidity and multimorbidity between these conditions [22‐24]. Therefore, as the medical history of the family and the housing environment during prenatal and early life periods are possibly associated with the development of asthma and allergies [25‐27], similar associations may be seen in CI. Clarifying the environmental factors or predisposing causes associated with CI during these periods would enhance our understanding of CI and assist in the development of future strategies to prevent it. Considering those insights, the aim of this study was to investigate the background factors in family members and parent–child relationships that may influence the development of CI.

In the present study, the prevalence of CI in mothers and 3-year-old children is 4.5% and 0.25%, respectively. The prevalence of self-reported CI is rather high, 9 to 33%, whereas it drops to 0.5 to 6.3% when fulfilling the clinical criteria for CI [24]. A study by Black et al. using the same questionnaire and definition used in our study reported that the prevalence of CI was 2.6% in general military personnel (10.4% females, 89.6% males) [28]. Given that a preponderance of women among CI sufferers is almost consistently reported in population-based studies [16] and that a Japanese population-based study reported that the CI prevalence in females was approximately twofold higher than in males [1], the prevalence in mothers in this study suggests a similar level to that of the study by Black et al. [28]. Although one study reported that the age distribution of CI prevalence in teenagers was almost one third of that in young people in their 20s [20], to our best knowledge, the prevalence of CI in children under 10 years of age has not been reported. The present study shows that the CI prevalence in 3-year-old children is almost one eighteenth that of their mothers.

In the present study, cold sensitivity in mothers is significantly associated with CI in mothers. Cold sensitivity is a common symptom in Japanese women. Interestingly, cold sensitivity is observed in approximately one half of Japanese women, and it can lead to a decreased quality of life [36]. To the best of our knowledge, our result is the first reporting on this association among the studies looking at CI including MCS and IEI. Cold sensitivity is an elusive condition that has previously been defined as an exaggerated or abnormal reaction to cold exposure causing discomfort, including symptoms involving the central nervous system, respiratory, gastrointestinal, musculoskeletal, and peripheral vascular problems, that can be accompanied by pain, numbness, stiffness, weakness, and swelling. The pathophysiological mechanisms are not fully elucidated but seem to involve a multifactorial etiology, including neural, vascular, and humoral aspects; disturbance of the autonomic system; lifestyle; and psychological stress [36, 37]. The etiology of peripheral coldness is also not well established, but it may be associated with decreased peripheral blood flow [38]. Symptoms of fibromyalgia can arise from peripheral influences of the autonomic nervous system in response to aversive mood states (e.g., anxiety, fear, sorrow, and depression) [39] that are relatively common chronic conditions with CI [40, 41]. Stress, when chronic, results in cardiovascular dysfunction with reduced peripheral blood flow due to vasoconstriction [42, 43]. The resting levels of peripheral vasoconstriction are particularly high for women relative to men [44‐46], and CI is primarily a disorder in women [1, 16]. Therefore, understanding the association of CI with cold sensitivity, especially peripheral influences of the autonomic nervous system, may provide further insights into the underlying mechanisms of CI.

The present study indicates that asthma and allergies are significantly associated with CI, which is consistent with several previous studies [1, 24, 47, 48]. Unregulated ingestion of meals is significantly associated with CI. A recent study reported that a high percentage of patients with CI had a poor nutritional status, low muscle strength, and decreased muscle mass [49]. Whether these changes are the cause or a consequence of CI, however, remains unclear.

In the present study, the presence of an indoor cat during childhood is significantly associated with current CI in mothers, but the association is weak compared with cold sensitivity and past asthma and allergies. In allergic diseases, systematic reviews suggest that the overall cumulative evidence shows no increase in risk of allergic disease from early exposure to pet allergens [26], with a possible decreased risk of asthma associated with cat allergen exposure in one study [50]. Therefore, early exposure to pet allergens is not likely to be associated with the development of CI. Rather, early exposure to odor or irritant substances emitted from excrement of pets, including body odor, urine, or feces, may be associated with the development of CI.

The present study indicates that current CI of mothers is significantly associated with allergic rhinitis, bronchial asthma, and chronic bronchitis of 3-year-old children. A study reported that a high percentage of patients with CI had a poor nutritional status [49]. In the present study, unregulated ingestion of meals is significantly associated with CI. Nutrition in early life is associated with risk of asthma and allergic disease [51‐53]. The nutritional status in mothers with CI may be affecting the respiratory hypersensitivity of the children. Otherwise, poor housing conditions due to lower socioeconomic status may increase the exposure to indoor environmental allergens associated with asthma and rhinitis, including microbial agents, house dust mites, pests, or molds, during early life [26]. The CI of mothers is significantly associated with the CI of children in all tested models, although only a few variables were tested because of the small number of 3-year-old children with CI. One study suggested that exposure to tobacco smoke, disinfectants, or volatile organic compounds in the first year of life contributed to an enhanced risk for the development of wheezing symptoms within the second year of life [54]. However, patients with CI attempted to avoid exposure to odorous chemicals as much as possible in their daily life [13‐15]. Therefore, further investigations on these associations in the maternal lifestyle and housing environment during the prenatal period in mothers and in the early life of the children are needed.

A recent study reported that avoidance behavior related to odorous and/or pungent chemicals has increased in persons with CI. The environmental risk factors related to CI have become diversified in the past decade due to lifestyle changes and the development of novel household products and building materials [55]. Therefore, the endogenous and/or exogenous causes of CI and the underlying mechanisms of CI need to be identified. This will be very important in preventing CI and improving the quality of life for those experiencing CI. Our findings can provide novel and progressive insights on these issues in CI.

There are some limitations associated with our study. First, because the study design is a cross-sectional retrospective, it is difficult to determine the cause and effect of temporal relationships. Second, this study is based on self-reported responses to a questionnaire. The environmental reports from the participants are highly subjective, and the resulting inaccuracies may result in bias. This is also true of the subjective, self-reported CI assessments used in this study, despite the use of a well-known questionnaire that has been developed by a panel of physician experts. Third, although we attempted to discriminate between current CI of 3-year-old children and current CI and past medical history of the mother and father, only a few variables could be tested because of the small number of 3-year-old children with CI. Further large-scale study is required to examine the factors related to development of CI in 3-year-old children.

We estimate that the prevalence of CI in 3-year-old children is almost one eighteenth of that experienced by their mothers. Our finding suggests that inherent physical constitution, especially cold sensitivity, is associated with the risk of acquiring CI. We also suggest that the presence of an indoor cat during childhood may be associated with a risk of acquiring CI. Children of mothers with CI have a possible risk of respiratory hypersensitivity or inflammation. Understanding the association of CI with cold sensitivity, resulting in peripheral influences of the autonomic nervous system, may provide further insights into the underlying mechanism of CI. The relationships between the CI of mothers and respiratory hypersensitivity or inflammation and the CI of their children are interesting. Characteristics of inherent physical constitution may affect those relationships. Further investigation of the inherent physical constitution and background environmental factors associated with risk of acquiring CI, especially during the prenatal period in the mother and in the early life of the children, is required. The impact of having mothers with chemical intolerance on the health of children also requires further study.