Regulatory Toxicology and Pharmacology 90 (2017) 231e243

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Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/yrtph

Cleaning and asthma: A systematic review and approach for effective

safety assessment
Melissa J. Vincent*, Ann Parker, Andrew Maier
Department Environmental Health, University Cincinnati College of Medicine, Cincinnati, OH, USA

a r t i c l e i n f o a b s t r a c t

Article history: Research indicates a correlative relationship between asthma and use of consumer cleaning products. We
Received 18 November 2016 conduct a systematic review of epidemiological literature on persons who use or are exposed to cleaning
Received in revised form products, both in occupational and domestic settings, and risk of asthma or asthma-like symptoms to
6 July 2017
improve understanding of the causal relationship between exposure and asthma. A scoring method for
Accepted 10 September 2017
assessing study reliability is presented. Although research indicates an association between asthma and
Available online 14 September 2017
the use of cleaning products, no study robustly investigates exposure to cleaning products or ingredients
along with asthma risk. This limits determination of causal relationships between asthma and specific
Keywords:
Asthma
products or ingredients in chemical safety assessment. These limitations, and a lack of robust animal
Hazard characterization models for toxicological assessment of asthma, create the need for a weight-of-evidence (WoE) approach
Cleaning to examine an ingredient or product's asthmatic potential. This proposed WoE method organizes diverse
Systematic review lines of data (i.e., asthma, sensitization, and irritation information) through a systematic, hierarchical
Acetic acid framework that provides qualitatively categorized conclusions using hazard bands to predict a specific
Weight of evidence product or ingredient's potential for asthma induction. This work provides a method for prioritizing
Sensitization chemicals as a first step for quantitative and scenario-specific safety assessments based on their potential
Irritation
for inducing asthmatic effects. Acetic acid is used as a case study to test this framework.
© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction (RADS; Bernstein, 1993; Vandenplas et al., 2014) or Low Intensity

Asthma prevalence is rising globally. Approximately 7% of adults
(17.7 million) and 8.6% of children (6.3 million) in the United States
have been diagnosed with current asthma, increasing the burden
on health care costs and impacting quality of life (Centers for
Disease Control and Prevention (CDC), 2015). Asthma is a com-
plex syndrome with multiple phenotypes (Bousquet et al., 2010)
characterized by a combination of smooth muscle dysfunction and
inflammatory responses (Lemanske and Busse, 2010; NHLBI, 2007)
that commonly presents with symptoms of cough, wheeze, dys-
pnea, and chest tightness (Tarlo et al., 2008; Association of
Occupational and Environmental Clinics (AOEC), 2008). Most
cases of asthma are caused or triggered by specific (IgE–mediated)
or non-specific (IgE-independent) inflammation (Mapp et al.,
2005), but exposures to chemical irritants can also cause asthma-
like syndromes, like Reactive Airways Dysfunction Syndrome
* Corresponding author. University of Cincinnati College of Medicine, 160 Panzeca
Way, Cincinnati, OH 45267, USA.
E-mail address: melissa.vincent@uc.edu (M.J. Vincent).
Chronic Exposure Dysfunction Syndrome (LICEDS; Baur et al.,
2012). Thus, understanding the subtleties of evaluating asthma as
an endpoint in the safety and risk assessment context is an
important undertaking. However, risk assessors are hampered by
limitations in both epidemiology and toxicology methods, specif-
ically a lack of reliable in vitro or in vivo models for asthma or
asthma-specific risk assessment guidance (Maier et al., 2014; 2015)
and inadequate exposure characterization.
Interpretation of the potential for cleaning products or indi-
vidual ingredients to induce asthma (i.e., cause new-onset asthma)
or elicit an asthmatic response is an important driver for product
formulation decisions and regulatory outcomes. The use of cleaning
products in residential and commercial applications is implicated
as a potential inducer of asthma or as a trigger for respiratory
symptoms in asthmatics, which may contribute to the observed
morbidity (Zock et al., 2010; Folletti et al., 2014; Jaakkola and
Jaakkola, 2006; Siracusa et al., 2013). Current evidence is not suf-
ficiently robust to accurately characterize the mixture of chemicals
and exposures encountered during cleaning, nor to determine a
clear relationship between specific cleaning product exposures and

http://dx.doi.org/10.1016/j.yrtph.2017.09.013
0273-2300/© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
232 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243
Abbreviations
AIHA American Industrial Hygiene Association
AOEC Association of Occupational and Environmental Clinics
CDC Centers for Disease Control and Prevention
ETS Environmental Tobacco Smoke
EU European Union
HCL Hydrochloric Acid
IgE Immunoglobulin E
JEM Job Exposure Matrix
LCL Lower Confidence Limit
LICEDS Low-Intensity Chronic Exposure Dysfunction
Syndrome
the development of asthma, or asthma induction. Cleaning-related
exposures are complex; cleaning can expose individuals to chem-
ical irritants and also temporarily increases intake of dusts, pollen,
dander, and molds while simultaneously reducing overall house-
hold allergen burdens over time (Nickmilder et al., 2007; Zock et al.,
2009; Hern
andez-Cadena et al., 2015). Some studies have con-
ducted quantitative exposure assessments of cleaning scenarios
(Bello et al., 2010; Vincent et al., 1993; Nazaroff and Weschler, 2004;
Singer et al., 2006; LeBouf et al., 2014; Bessonneau et al., 2013), but
none measured asthmatic or asthma-like outcomes for determi-
nation of a quantitative exposure-response relationship.1 Without
linking quantitative exposure assessments to asthma response, the
exposure-response relationship between cleaning product in-
gredients and asthma cannot be characterized and drawing con-
clusions about specific causal relationships is limited (Hill, 1965;
Meek et al., 2014). Thus, the absence of definitive exposure-
response data is hindering advances in risk management of
cleaning-related asthma.
Due to the lack of specificity between cleaning activities and
asthma induction and, more specifically, a lack of quality quanti-
tative exposure-response estimations, risk assessors are limited to
the use of ingredient-specific (i.e., single chemical) toxicological
information. However, in the case of asthma, there is no single
validated asthma animal model and assessments often use surro-
gate endpoint data (e.g., sensitization and irritation). This study
aims to develop a weight-of-evidence (WoE) approach that can be
used to integrate multiple lines of imperfect evidence. We devel-
oped a series of risk assessment tools to address this challenge,
specifically a multi-step decision system with sequential data
analysis techniques and a systematic framework for evaluating
weight of evidence to inform hazard characterization and prioriti-
zation decisions (Fig. 1). This prioritization framework is divided
into four key steps: systematic review, hazard characterization,
safety assessment, and risk management. The procedure uses
diverse lines of evidence, specifically human data on asthma and
human and animal data on sensitization and irritation to establish a
weight-of-evidence category. These tools include an objective
study quality evaluation approach that rates epidemiological
studies according to their reliability and relevance for asthma safety
and risk assessment. Although many high-quality guidelines for
evaluating the quality of epidemiological studies exist, they are
1
Medina-Ramon et al. (2005) collected short term personal exposure measure-
ments of airborne chlorine and ammonia in a subsample of 10 subjects (four cases
and six controls). These ad-hoc measurements were used to describe common
exposures and not to compare exposure levels between cases and controls or to
determine a dose-response relationship.
LRTS Lower Respiratory Tract Symptoms
NHBLI National Heart, Lung, and Blood Institute
NTP National Toxicology Program
OR Odds Ratio
PR Prevalence Ratio
RADS Reactive Airways Dysfunction Syndrome
RR Risk Ratio
SES Socioeconomic Status
TERA Toxicology Excellence for Risk Assessment
TRP Transient Receptor Potential
UCL Upper Confidence Limit
URTS Upper Respiratory Tract Symptoms
WoE Weight of Evidence
generally tailored for specific uses (i.e., biomonitoring or exposure
evaluation (LaKind et al., 2014)), disease outcomes (e.g., the Quality
Assessment of Diagnostic Accuracy Studies (QUADAS) for neuro-
developmental studies (Whiting et al., 2003)) or scenarios not
relevant for asthma risk assessment. Other guidelines are complex
and difficult to interpret and use in a WoE tool that integrates
multiple lines of evidence because they lack a method for ranking
studies by their quality. Examples include the BEES-C (LaKind et al.,
2014), the PRISMA statement for reporting systematic reviews and
meta-analyses (Liberati et al., 2009), the OHAT approach (NTP,
2013), the STROBE statement (Von Elm et al., 2008), and the
RCGP three-star system (Nicholson et al., 2010; Baur, 2013). Our
approach aligns with the underlying principles of such methods,
but was customized to be flexible and simple in interpretation and
easy to integrate with the Klimisch et al. (1997) scoring system
widely used for toxicological study evaluation. The approach is
expected to facilitate chemical safety assessment.
Our approach includes a systematic review of current epide-
miology literature using the quality evaluation tool. The purpose for
this review was two-fold: 1) to validate the proposed quality
evaluation method and 2) to determine if persons (both adults and
children) with and without a history of pre-existing asthma who
actively use or are exposed to domestic cleaning products, both in
occupational and domestic settings, at least one time per week are
at increased risk for asthma or asthma-like symptoms during their
lifetime. Domestic cleaning products are defined as products that
are commonly available, can be purchased “off the shelf” at local
stores, and are typically used in home cleaning scenarios. Specif-
ically, we apply Bradford Hill's criteria for causal association in a
chemical safety assessment context (Hill, 1965; Meek et al., 2014) to
assess the strength, consistency, temporality, and coherence of the
observed associations between cleaning product ingredient expo-
sures and new-onset asthma.
In addition to our presentation of this systematic framework, we
apply the methodology to a case study on acetic acid to test the
robustness and accuracy of the method (refer to Supplemental
Material 1). It is our goal that these methods can be used to enhance
understanding of the possible relationship between cleaning
product ingredients and asthma despite the knowledge gaps and
lack of robust exposure-response information.
2. Methods
The proposed framework for characterizing and prioritizing
chemicals based asthma hazard using a weight-of-evidence
method is a multi-step process (see Fig. 1). The proposed
methods provide guidance for navigating the first two steps of the
 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243
Fig. 1. An overview of a multi-step asthma hazard and exposure assessment approach.
framework: systematic review and hazard characterization. The
third and fourth steps, safety assessment and risk management, are
described in detail in Maier et al. (2015).
2.1. Step 1: study Quality Assessment and categorization
The initial step of the proposed multi-step asthma hazard and
exposure assessment approach (see Fig. 1) is to conduct a system-
atic review of the literature. In this approach, toxicology data are
reviewed and ranked using the Klimisch method for assessing
reliability (Klimisch et al., 1997). Relevant epidemiology studies are
critically reviewed and categorized by an internally developed
scoring method based on the modified Hill Criteria (Meek et al.,
2014), the principles developed by Klimisch et al. (1997), and
standard epidemiological evaluation practices incorporating the
internal and external validity of each study (Lewandowski and
Rhomberg, 2005; Money et al., 2013). Studies are assigned a score
ranging from 1 to 4, depending on their reliability and relevance for
use in risk assessment (see Table 1 for a description of the scores,
their categories, and their interpretation). Reliability, in the context
for this report, is defined by the strength of the study design and its
ability to validly address the hypothesis of exposure and adverse
respiratory health outcome(s). Lower scores are indicative of a
more reliable study. Key confounders and effect modifiers should
be selected a priori, but can be modified to meet the individual
needs of each chemical-specific scenario. Fig. 2 depicts the decision
process involved in assigning a study score.
Table 1
A detailed description of the scores assigned to each reviewed epidemiological study.
Score Definition
1 Relevant and reliable without restriction
2 Relevant and reliable with restrictions
3 Relevant, but not reliable for this assessment
4 Relevant, but reliability cannot be determined from limited
documentation. Not useful for this assessment
233
This scoring method was designed to match the categories
proposed by Klimisch et al. (1997) so that epidemiology and toxi-
cology evidence can be used concordantly in a WoE evaluation.
However, other study quality evaluation methods can also be
adapted and used with the proposed WoE and safety assessment
methods, as needed. For example, scenarios with complex exposure
considerations (e.g., biomarkers) could adopt concepts from the
BEES-C method (LaKind et al., 2014) to evaluate exposure mea-
surement quality in more depth than the proposed method, which
is based only on categorical judgments regarding population,
duration, and temporal patterns (see Fig. 2).
Although this system is intended for use in chemical-specific
assessments, we conduct a systematic review of the current, rele-
vant epidemiology literature to test and validate the method across
a large sample of studies and provide a detailed example of its
intended use. A series of terms that relate to both the symptoms
and diagnosis of asthma (e.g., wheezing, asthma and airway hy-
perreactivity) were searched, in conjunction with terms that
describe various facets of cleaning products (e.g., laundry and
dishwashing), in the National Library of Medicine databases
PubMed and TOXLINE. Additional details, including search terms,
databases, and inclusion and exclusion criteria are included in the
Supplemental Material, Section 1. We included any study that
assessed the prevalence of asthma or respiratory symptoms that
might be expected from an asthmatic response, referred to as
asthma-like symptoms, in both domestic and occupational
cleaners. Studies involving persons regularly exposed to sensitizers
Interpretation
A study that is both internally and externally valid. A longitudinal study that addresses key
confounders and biases and is relevant to the population of interest.
A study that is most likely internally and/or externally valid. A study that may or may not address
key confounders or biases and may or may not directly evaluate the population of interest.
A study that is likely not internally and/or externally valid. A study that does not address key
confounders or biases or directly measure the endpoint of interest, and/or is not directly evaluating a
population of interest.
A study that is a literature review or a study with very poor study documentation that precludes
evaluating the robustness of its findings.
234 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243
Fig. 2. A description of the decision-making process used for determining the quality (score) of an individual epidemiology study.
that are not ingredients found in domestic cleaning products (i.e.,
nurses who work with glutaraldehyde, Chloramine-T, chlorhexi-
dine, formaldehyde, or benzalkonioum chloride) were excluded
(e.g., Lipinska-Ojrzanowska et al., 2014, 2017). Studies involving
persons working in manufacturing of cleaning products were also
excluded (e.g., Abdel Salam et al., 1966; Pham and Mire, 1978;
Oleru, 1984; Hendrick et al., 1988; Bernstein et al., 1994).
Although these studies and case reports may be useful for the
assessment of health effects and risk associated with specific
products (e.g., detergent soaps) or ingredients (e.g., acetic acid, as
shown in the case study), the associated exposure levels and du-
rations are likely drastically higher than those encountered by
cleaners who use domestic products. For this review, we did not
include information regarding enzyme detergents. Only English-
language studies were considered.
For this review, only physician-diagnosed cases were considered
to be confirmed cases of asthma. We separately analyzed studies
that included clinically-diagnosed cases of asthma from those that
only evaluated non-specific symptoms. Studies including in-
dividuals with no prior diagnosis of asthma (i.e., new-onset asthma
cases) were evaluated regardless of underlying etiology (e.g.,
immunogenic or non-immunogenic). We also included studies on
prevalence of respiratory symptoms expected from an asthmatic
response, referred to as elicitation or exacerbation of asthma-like
symptoms. Key confounders and effect modifiers are considered
2
Other factors are linked to asthma response, specifically parental history of
atopy or the presence of household pets, but were not used to judge a study's
reliability. The key confounders and effect modifiers listed here are intended to
represent the minimum of factors that should be considered in a robust epidemi-
ological study on asthma response.
to be age, race, sex, smoking status, socioeconomic status (SES, a
predictor of household indoor air quality), and atopy.2
2.2. Step 2: weight of evidence and hazard characterization
methodology
The steps in the overall WoE process are shown in Fig. 3. Because
no validated animal models for asthma currently exist, evidence of
respiratory sensitization or irritation in animals are evaluated as a
potential precursor or inducer of asthma. The analysis assumes one
can infer likely respiratory tract responses from assays that involve
exposures by routes other than inhalation (e.g., dermal). However,
since inhalation data are often not available, the method accom-
modates the use of data from other routes. The use of surrogate
health endpoints for asthma and non-inhalation routes of exposure
are reflected in the data hierarchies applied in the WoE process.
Respiratory sensitization is categorized as either present or ab-
sent in the WoE analysis. To assess respiratory sensitization po-
tential, multiple lines of evidence are used. Epidemiology studies,
case reports and controlled exposure studies in volunteers are
given more weight. However, for most chemicals, human effects
data on respiratory sensitization are not available. Because there
are no fully validated, predictive tests available to identify with a
high degree of specificity whether or not a chemical is a respiratory
allergen in humans (Anderson et al., 2011; Dotson et al., 2015;
Kimber et al., 2011), the WoE also includes findings from stan-
dard sensitization protocols, including those conducted via the
dermal route. Due to the complexity of the immune system, species
differences in respiratory tract and immune system physiology and
anatomy, and experimental challenges involved in conducting
inhalation exposure experiments compared to dermal application
studies (Arts et al., 2006; Pauluhn et al., 1999), validated, predictive
 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243
Fig. 3. Weight of Evidence (WoE) Analysis Process for Potential Chemical Asthma Hazards. The process incorporates multiple lines of evidence. The data are sorted by endpoint to
align with endpoint specific WoE categorizations that are combined to inform the overall asthma hazard characterization. Data are arrayed showing highest weight (i.e., greater
value to the determination of asthma potential) at the top of each column.
animal models are lacking.
The ability of a chemical to trigger asthma-like responses is
assumed to correlate with the degree of irritation it induces.
Because there are inherent uncertainties in extrapolating from
irritant potential to asthma potential, data on irritation are placed
in one of two broad categories to avoid the suggestion of an un-
warranted level of precision in the WoE procedure. Respiratory
irritation potential is categorized as (1) none or mild and (2)
moderate or severe. The degree of irritation induced by a chemical
used for the WoE generally reflects the response to the neat ma-
terial, although concentration dependent responses are noted
when such data are available and as relevant to use scenarios
subject to the assessment. This approach of lumping irritation into
two categories reflects the intended use of the method to identify
chemicals likely to have the potential to cause or elicit asthma re-
sponses and prioritize them for more in-depth analysis or data
collection.
In the absence of adequate respiratory effects data, data from
standard irritation protocols (skin, ocular, and in vitro-based
methods) are used to predict respiratory irritation potential.
Although eye, skin, and respiratory responses do not always
correlate well (Levy and Wegman, 1988), sensory irritants may act
locally in the skin, eye, and respiratory tract mucosae through
shared mechanisms which mediate sensations of irritation
(Ballantyne, 1999). Rennen et al. (2002) determined that skin and
eye irritants frequently acted as respiratory irritants. Correlations
between standard eye irritancy tests and respiratory tract irritancy
showed a quantitative relationship between Draize eye scores (eye
irritation) and respiratory tract irritant effect levels (Cometto-
Muniz et al., 2010; TERA, 2010). For some types of irritants, the
underlying mechanisms are likely to be consistent across routes.
Such mechanisms may include direct tissue reactivity for corrosive
substances (e.g., hydrochloric acid) or activation of transient re-
ceptor potential (TRP) ion channels present in nociceptive neurons
and various epithelial tissues (e.g., capsaicin, mustard oil) (Caterina
et al., 1997; Jordt et al., 2004; Katagiri et al., 2015).
For each endpoint (asthma, respiratory sensitization, respiratory
irritation) a likelihood categorization is assigned based on the WoE
(see Table 2, Fig. 4). Individual studies are evaluated for reliability
and relevance (see section 2.1) and are assigned a strength of evi-
dence categorization (Table 2). Although the integration of indi-
vidual studies and lines of evidence in the WoE assessment reflects
235
the general preference for human inhalation studies, these general
preferences are balanced with other considerations related to in-
dividual study quality. The endpoint descriptors reflect the
robustness of the database identified for each endpoint based on
the WoE from the available data.
After assigning a strength of evidence categorization for each of
the individual endpoints (asthma, sensitization, and irritation, see
Table 2), the individual endpoint categories are used to assign a
categorization for the overall WoE for asthma (Table 3). Evidence of
respiratory sensitization and irritation in humans is weighed more
heavily than in animals when deciding the overall WoE for each
chemical. Evidence of respiratory effects (sensitization and irrita-
tion) is weighed more heavily than evidence of dermal effects.
Although dermal irritation and sensitization data are potential
surrogates in the absence of respiratory irritation and sensitization
data, the two endpoints are not completely correlated, which adds
additional uncertainty to the evaluation.
The overall WoE categorizations can be used as a hazard-based
prioritization tool for selecting cleaning product ingredients that
are most likely to elicit or induce an asthmatic response and,
therefore, need additional assessment. This approach is intended to
be conservative and health-protective.
The next steps of the framework for characterizing and priori-
tizing chemicals (see steps 3 and 4 of Fig. 1) are safety assessment
and risk management. We have proposed, elsewhere, a tiered
safety assessment that integrates both hazard information
(including quantitative exposure guidance benchmarks) and
exposure assessments that can incorporate cleaning-specific sce-
narios (see Maier et al., 2015 for methods and details). This tiered
approach allows for assessment of most chemicals and scenarios by
using lower tiers designed to be precautionary for screening
assessment purposes.
3. Results
3.1. Literature review
Our literature search (including tree, or backwards, literature
searching) identified 1157 studies related to asthma and cleaning
(see Fig. S1 in Supplemental Material 1 for additional details). Based
on a review of titles and abstracts, 148 were determined to be
potentially relevant for the scope of this assessment. Of these
236 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243

Table 2
Categorizations for describing the strength of evidence, both for each individual study and the overall likelihood based on WoE of all studies, that a chemical causes asthma,
respiratory sensitization, or irritation.

Strength of Asthma Respiratory Sensitization Respiratory Tract Irritation

Evidence
Categorization

Likely There is evidence of a statistically significant There is evidence of a statistically significant This chemical is likely to be a moderate or severe
positive asthmatic effect following exposure to positive sensitization effect in humans by the respiratory irritant. This descriptor is used for
this chemical. This descriptor reflects data sets inhalation route. This descriptor also reflects data chemicals with a high irritancy or corrosive
with strong evidence to induce asthma or asthma- sets with one or more standard assays (including potential based on inhalation data or very strong
like responses in humans and/or in animal models those via dermal application) or data sets showing indirect evidence from skin or ocular irritancy
in conjunction with, at minimum, weak evidence high sensitization potential or data sets where a information with a mode of action that is likely to
of asthma in humans. preponderance (i.e., a clear majority) of studies be relevant across routes.
show sensitization potential supported by limited
human effects information.
Suggestive There is convincing, but not strong evidence of a There is evidence of a positive effect, but it is not This chemical has evidence that suggests it may be
positive asthmatic effect. This descriptor reflects strong. This descriptor reflects data sets with a moderate to severe respiratory irritant, but a
data sets with reports of marginal effectsa and/or reports of marginal effects and situations where mild irritancy potential is also probable under
situations where overall data are of limited quality overall data are of limited quality, or provide some conditions consistent with chemical use.
or provide mixed or inconsistent evidence for an mixed or inconsistent evidence for an effect.
effect. Generally, no reliable evidence following
inhalation is available or positive inhalation
studies are contradicted by high quality
sensitization assays.
Unlikely There is strong evidence of an absence of an There is strong evidence of an absence of effect. This chemical is unlikely to be a moderate to
asthmatic effect following exposure to this This descriptor reflects data sets with multiple severe respiratory irritant. It is shown to have only
chemical. This descriptor reflects data sets with standard bioassays showing negative results or a a mild or no irritancy potential following
strong evidence that the chemical does not induce data set where a preponderance (i.e., a clear inhalation or based on a robust data set from skin
asthma or asthma-like responses in humans and/ majority) of studies shows no significant effect or eye irritation studies at concentrations
or strong evidence that the chemical does not supported by negative findings in human effects consistent with chemical use.
induce asthma or asthma-like responses in studies.
animals in conjunction with an absence of asthma
in humans.
Inadequate This descriptor reflects data sets that are too This descriptor reflects data sets that are too This descriptor reflects data sets that are too
limited to evaluate the endpoint directly limited to evaluate the endpoint. limited to evaluate the end point.
a
Marginal effects are defined as risk ratios or test results (e.g., ANOVA) that are not statistically significant, but are reasonably close (i.e., a p-value of 0.06 or an OR LCL of
0.99). Although these results are not statistically significant, this lack of significance may be due to study design issues, such as insufficient power, or study variability. In order
to be health-protective, this method is conservative in its approach and does not consider borderline, or marginal, LCLs or p-values to be strong evidence of a lack of effect.
Since this is a screening approach, it is preferred to err on the side of caution and potentially mislabel chemicals as asthma inducers, rather than the converse.

studies, 69 were reviewed and included for consideration in this
assessment (i.e., given a reliability score of 1e3. Studies given a
score of 4 were not included). Of the 69 reviewed studies, 17 were
case studies or case series (see Supplemental Material 1 for addi-
tional details including inclusion and exclusion criteria).
An ideal study was defined as one that evaluates the incidence
of asthma through a definitive diagnosis (i.e. determined by a
physician through standard clinical criteria including lower respi-
ratory tract symptoms and bronchial hyper-responsiveness deter-
mined by spirometry before and after bronchodilators and/or
methacholine challenge) and quantitatively measures exposures
potentially associated with an asthmatic response. The current
database, however, contains no such study. No study, to date, has
quantitatively linked exposure to asthmatic response. Some studies
do use categorical exposure metrics to assess dose-response
regarding either the duration of occupational exposure (e.g., de
Fatima Macaira et al., 2007) or frequency of product use (e.g.,
Zock et al., 2007), but these consider neither specific ingredients
nor concentration, hindering their utility for use in safety and risk
assessment.
The group of most reliable studies (scored as 1 or 2) considered
jointly provide some indication of increased risk of developing
asthma and asthma-like symptoms among cleaners, although these
findings are not consistent (Table 4, Fig. 5, See Section 2 of the
Supplemental Material 1, Tables S2 and S3, for additional study
reviews, details and scores); the majority of odds ratios (ORs) are
greater than 1, indicating a possible trend of increased risk among
cleaners, but the statistical significance of the results is mixed.
Moreover, the strength of the significantly positive associations
between cleaning and asthma are moderate (i.e., an OR of
approximately 2.5 or less), especially in studies that assess
physician-diagnosed asthma. This is also generally true for studies
that assess self-reported asthma with the exception of Medina-
Ramon et al. (2005), which reports an OR of 12 (95%CI 3.2e46)
among non-domestic workers. Besides this exception, there is no
apparent difference in effect among studies that base their con-
clusions on physician-diagnosed asthma versus those that rely
solely on self-reporting (Table 4). Combined with a lack of robust
dose-response information, the currently available evidence is not
sufficient to establish causal relationships between exposure to
cleaning agents and new onset asthma. Additional research on
exposure, including non-chemical (e.g., aeroallergens, such as
pollen or mold) contributions, associated with cleaning tasks is
needed.
The epidemiology data, based on the Hill criteria, indicate that
there is a positive, but limited relationship between cleaning and
asthma due to an inability to establish causality (Table 5).
3.2. Case study: acetic acid
To test our proposed framework, we conducted a case study
using acetic acid as an example. Acetic acid was chosen because it is
data-rich and commonly used as an ingredient in both commercial
and home-made (i.e., vinegar-based) cleaning products, is a known
irritant, and was labeled an “asthmagen” by the AOEC (2012).
As indicated in Fig. 1, the first step of this multi-step hazard
characterization approach is to assess, through systematic review,
whether there is evidence of a potential asthma hazard in a human
 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243
Fig. 4. The decision-making process used for categorizing the strength of evidence for each individual study and the weight of evidence for a chemical's database of asthma
elicitation, respiratory sensitization, or respiratory irritation information.
exposure environment. As indicated above, the larger database of
epidemiological assessments indicated a link between cleaning and
asthma. Many cleaning products including acetic acid as an ingre-
dient were used or evaluated in the epidemiological literature. No
definitive causal link can be determined from the currently avail-
able information on cleaning activities. Therefore, an ingredient-
specific hazard assessment is warranted.
See section 3 of the supplemental material for a detailed
example of this framework using acetic acid as a case study. A
summary of the findings is shown in Table 6. Because this hazard
assessment indicates that acetic acid, as neat, undiluted material, is
likely to induce or exacerbate asthma, a more definitive safety
assessment would be conducted. A scenario-specific safety
assessment is presented by Maier et al. (2015) for acetic acid.
4. Discussion
4.1. Framework challenges and considerations
Our systematic review found a positive association between use
of domestic cleaning products and asthma response, consistent
with the findings of Siracusa et al. (2013) and Folletti et al. (2014).
However, the evidence linking exposure to cleaning agents as a risk
3
This review and our subsequent conclusions do not include manufacturing
exposures.
237
factor for causing new onset asthma is limited, based on application
of the Hill Criteria (Hill, 1965; Meek et al., 2014).3 A number of the
Hill Criteria are not fulfilled, specifically consistency/concordance,
dose-response, strength of the association, and specificity of the
association (Table 5). Due to the lack of robust quantitative expo-
sure analysis, no exposure-response relationship between potential
exposures and new onset asthma can be ascertained from the
currently available data. Moreover, cleaning exposures are not
specific to cleaning product ingredients, and may include a number
of other potential risk factors, such as increased airborne dust and
microbial exposures (Knibbs et al., 2012). Although the causal
relationship between asthma induction and use of cleaning prod-
ucts is unclear, it is biologically plausible and disease prevention
strategies should be used until additional information on specific
risk factors, effect mechanisms, and exposure characterizations and
quantifications is obtained (Siracusa et al., 2013).
There are multiple surrogates for exposure (e.g., the number of
products used, or duration of cleaning activity, or employment as a
cleaner), but their reliability for characterizing an exposure-
response relationship is uncertain. There are multiple scenarios
and circumstances in which surrogate exposure metrics would not
account for actual exposures. Specifically, product misuse (e.g.,
mixing bleach with acids) is not uncommon among cleaners
(Medina-Ramon et al., 2005; Zock et al., 2001) and may play a large
role in the onset of respiratory disease including asthma, as is
evidenced by multiple case reports/series (Deschamps et al., 1994;
238 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243

Table 3
A decision matrix for determining the overall weight of evidence for asthma induction potential based on the weight of evidence categorization for each individual endpoint,
specifically asthma, moderate to severe respiratory irritation, and respiratory sensitization.

Asthma Respiratory Sensitization Respiratory Irritation Overall WoE Categorization for Asthma

Likelya Any Category Any Category* Likely

Suggestiveb Likely Likely Likely
Suggestive Suggestive Any Category Suggestive
Suggestive Inadequate Any Category Suggestive
Suggestive Unlikely Any Category Suggestive
Inadequatec Likely Likely Likely
Inadequate Likely Suggestive Suggestive
Inadequate Likely Inadequate Suggestive
Inadequate Likely Unlikely Suggestive
Inadequate Suggestive Likely Suggestive
Inadequate Suggestive Suggestive Suggestive
Inadequate Suggestive Inadequate Suggestive
Inadequate Suggestive Unlikely Inadequate
Inadequate Inadequate Likely Inadequate
Inadequate Inadequate Suggestive Inadequate
Inadequate Inadequate Inadequate Inadequate
Inadequate Inadequate Unlikely Inadequate
Inadequate Unlikely Likely Inadequate
Inadequate Unlikely Suggestive Inadequate
Inadequate Unlikely Inadequate Inadequate
Inadequate Unlikely Unlikely Unlikely
Unlikelyd Any Category Any Category Unlikely

*“Any Category” indicates that the same ultimate weight of evidence descriptor (i.e., likely, suggestive, inadequate, or unlikely) will be assigned regardless of the descriptor in
this endpoint.
Definitions of Overall WoE Descriptors.
a
“Likely” indicates robust evidence the chemical causes asthma in humans, or limited human evidence for inhalation exposures coupled with robust evidence that the
chemical is both a respiratory sensitizer and severe respiratory irritant (since these are potential asthma triggers).
b
“Suggestive” indicates evidence that suggests the chemical induces asthma or triggers asthma-like responses in humans, but it is not conclusive, or there is evidence of
respiratory sensitization and moderate-to-severe respiratory irritation in the absence of human asthma data.
c
“Unlikely” indicates there is strong evidence of lack of asthma potential in humans, or strong evidence of absence of respiratory sensitization and weak or no irritation
potential.
d
“Inadequate” indicates that available data are not sufficient to affirm whether or not the chemical can cause asthma. This reflects poor or non-existent data that this
chemical is related to asthma responses, or there is mixed or inconclusive evidence of respiratory sensitization and severe irritation, or there is a lack of information on asthma
and respiratory sensitization. “Inadequate” is a common descriptor in the asthma category due to the absence of validated animal or in vitro models for this endpoint and does
not infer the absence of required safety testing.

Gorguner et al., 2004; Mapp et al., 2000). Moreover, categorical
exposure assessments are neither capable of considering the
various mixtures of chemicals (some of which may be irritants or
sensitizers) to which cleaners are exposed nor able to account for
how the cleaning process may increase exposure to non-chemically
related aeroallergens (i.e., by allowing deposited allergenic partic-
ulates to re-suspend in the air).
The lack of a clear causal relationship between general cleaning
and asthma induction means that safety and risk assessments need
to more fully explore such relationships to inform risk manage-
ment. A logical common starting point is the safety evaluation of
individual consumer product ingredients and their potential for
inducing or exacerbating an asthmatic effect. With 2000 new
chemicals being introduced every year for use in consumer items
(NTP, 2016), it is impossible to comprehensively assess risks for
each use scenario for every possible ingredient. Some screening
tools are in development to rapidly predict exposure and dose es-
timates, specifically ExpoCast (EPA, 2016a) or ConsExpo (RIVM,
2006) which can be compared to toxicity predictions (e.g., Tox-
Cast (EPA, 2016b)). A framework for using and interpreting these
tools is provided by Maier et al. (2015). By using screening and
hazard characterization methods, such as the ones presented,
safety and risk assessors can identify product ingredients that pose
the greatest risk and focus efforts on higher priority assessments.
Data integration methods and weight-of-evidence schemes are
not new to safety and risk assessment (e.g., Mohapatra et al., 2010,
2011), but no widely accepted approach has been developed spe-
cifically for asthma risk assessment. Because of the complexities of
asthma, particularly the variation in induction modes of action (i.e.,
IgE-mediated versus non-IgE-mediated), a one-size-fits-all
approach to asthma risk assessment may not be sufficiently pro-
tective of human health. There is currently no asthma-specific risk
assessment guidance (Maier et al., 2014), and the use of risk
assessment for surrogate endpoints alone (i.e., the IPCS (2012)
guidance for immunotoxicity [sensitization] risk assessment) is
not sufficiently predictive for asthma induction prevention. The
methods proposed here and in Maier et al. (2015) address gaps in
asthma risk assessment and provide methods for screening and
assessment of possible asthma-inducing chemicals.
4.2. Case study: acetic acid
In the case study on acetic acid, we used our proposed frame-
work to 1) score the quality and reliability of individual toxico-
logical and epidemiological studies 2) identify the likelihood that
acetic acid causes endpoint-specific effects (e.g., asthma, respira-
tory sensitization, or respiratory irritation), and 3) identify the
overall weight of evidence for asthma induction potential. The re-
sults categorize acetic acid as likely to elicit or induce an asthmatic
effect and indicate the need for further assessment, using the tiered
hazard characterization and exposure assessment approach
detailed in Maier et al. (2015). These findings are consistent with
current risk assessment guidance classifications for acetic acid,
specifically the European Union's (EU, 2010) determination that
acetic acid is irritating and/or corrosive, dependent on concentra-
tion, and the AOEC (2012) determination that acetic acid is a res-
piratory sensitizer and “asthmagen”. Additional case studies need
to be conducted to further test the validity of this method.
 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243 239

Table 4
Summary of the literature on cleaning-related asthma that is considered reliable for assessment (score 1 or 2) .a

Study Subgroup Study Design Population Type OR LCL UCL Score

Physician-Diagnosed Asthma
Arif et al., 2003 NA cross-sectional occupational 2.37 0.53 10.58 2
Arif et al., 2009 NA cross-sectional healthcare 1.72 1.00 2.94 2
Arif and Delclos, 2012 NA cross-sectional healthcare 0.48b 0.10 2.41 2
Dumas et al., 2012 Men nested case-control healthcare 0.62 0.23 1.66 2
Women 1.04 0.64 1.7
Dumas et al., 2014 NA case-control occupational 2.16 1.03 4.54 2
Gonzalez et al., 2014 NA cross-sectional healthcare 2.26 0.95 5.35 2
Kogevinas et al., 2007* Work as a cleaner cohort occupational 1.71* 0.92 3.17 2
Exposure to cleaning products 1.80* 1.01 3.18
Le Moual et al., 2012 NA case-control domestic 1.85 1.16 2.94 2
Le Moual et al., 2014 Uncontrolled asthma after 12 mo exposure cross-sectional occupational 2.0 1.1 3.6 2
Uncontrolled asthma after 10-year exposure 2.3 1.4 3.6
Ng et al., 1994 Domestic cleaners case-control occupational 1.24 0.49 3.13 2
Municipal cleaners 1.91 1.22 2.99
Obadia et al., 2009 Men cross-sectional occupational 0.93 0.4 2.3 2
Women 1.00 0.4 2.3
Undiagnosed Asthma

dard et al., 2014
Be NA cross-sectional domestic 2.63 1.03 6.67 2
Eng et al., 2010 current asthma cross-sectional occupational 1.8 0.8 3.7 2
adult-onset asthma 1.3 0.5 3.5
de Fatima Macaira et al., 2007\ >0.92e3 years employment cross-sectional occupational 1.09 1.00 1.18 2
>3e6.5 years employment 1.28 1.01 1.63
>6.5 years employment 1.71 1.02 2.89
Ghosh et al., 2013 domestic helpers cohort occupational 1.79 1.02 3.14 2
office/hotel cleaners 1.82 1.34 2.48
Medina-Ramon et al., 2003 ever had asthma cross-sectional occupational 1.44 1.12 1.85 2
current asthma 1.73 1.44 2.07
Medina-Ramon et al., 2005 non-domestic case-control occupational 12 3.2 46 2
Mirabelli et al., 2007 disinfection cohort healthcare 1.29 0.7 2.36 2
Svanes et al., 2015 all cross-sectional occupational 1.47 1.22 1.77 2
1 year work 0.92 0.65 1.31
>1 e < 4 years work 1.44 1.05 1.97
4 years work 1.59 1.22 2.08
Vizcaya et al., 2011 current cleaners cross-sectional occupational 1.4 0.4 4.9 2
former cleaners 2.5 0.5 12
Zock et al., 2002 cross-sectional occupational 2.47 1.7 3.6 2

*Estimates are Risk Ratios (RRs).

OR - Odds Ratio; LCL e Lower Confidence Limit; UCL e Upper Confidence Limit.
a
The studies included in this table are limited to a selection of reliable (score 1 or 2) studies that assess the link between asthma and cleaning in adults. Studies that evaluate
asthma risks associated with specific cleaning product exposures (e.g., bleach or sprays) were reviewed, but are not included in this table. Additional studies that assess the link
between asthma-like symptoms and cleaning exposures were also reviewed and considered. Studies examining asthma and asthma-like symptoms (e.g., wheeze) in children
were also reviewed, but are not included in this table. See the supplemental material and Tables S2 and S3 for additional study reviews, details, and rationales for score
selection.
b
Results are reported for workers with occupational asthma. Information on work-exacerbated asthma is presented in the supplemental material.

However, this approach was designed to be health protective; it is patterns may cause respiratory allergy, but there is insufficient in-
more likely that the approach will falsely identify chemicals as formation to determine which pattern is of greatest relevance or
possible asthma inducers rather than miss asthma inducing concern (Dotson et al., 2015).
chemicals through the screening process. Other key areas of exposure uncertainty relate to the interplay
between chemical, biological, and other stressors associated with
cleaning. The act of cleaning may temporarily increase airborne
4.3. Conclusions
dust and microbial exposures (Knibbs et al., 2012), but the use of
cleaning products (e.g., bleach) reduces the levels of aeroallergens
Although the proposed framework is useful for assessing the
and asthma triggers (e.g., mold, mildew, pet dander, dust, mites) in
safety profile of product ingredients, these current efforts do not
the home over time. It may have a net beneficial effect by reducing
resolve the many lingering exposure-specific questions encoun-
aeroallergen-specific atopy and the risk of asthma induction or
tered in real-world product use scenarios. There are many
elicitation (Zock et al., 2009; Nickmilder et al., 2007; Hern
andez-
remaining questions spurred by the lack of quantitative informa-
Cadena et al., 2015; Hu et al., 2014). Although some sensitizing
tion on task-based and ingredient-specific exposures. Specifically,
and/or irritant product components may increase the risk of
there are large data gaps concerning the exposure make-up of
developing asthma, multiple studies show that cleaning, and the
combined exposures and mixtures (i.e., the use of multiple prod-
use of specific cleaning products like bleach, may actually decrease
ucts or tasks within one room or setting) and temporal patterns
the risk of developing asthma by reducing exposure to other known
(e.g., peak versus chronic exposures). There is growing evidence
household allergens (Barnes et al., 2008; Zock et al., 2009; Chen and
that non-routine, relatively high (i.e., peak) exposures, as well as
Eggleston, 2001; Matsui et al., 2003; Nickmilder et al., 2007).
chronic lower-concentration exposures, may both contribute to
Overall, the use of cleaning products may reduce the risk of IgE
asthma (e.g., RADS or LICEDS). This is consistent with our knowl-
mediated asthma associated with living in a “dirty” environment
edge of the contributions of long versus short-term patterns of
while possibly increasing the risk of asthma induction or elicitation
exposure associated with allergic sensitization; both temporal
240 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243

Fig. 5. A forest plot depicting the results (ORs with 95% CI) for reliable (score 1 or 2) studies that examine the relationship between general cleaning tasks and physician-diagnosed
asthma. See Supplemental Material for additional study reviews and details.

Table 5
Application of the Hill criteria to the epidemiological database on cleaning and asthma.

Criterion Conclusion

Concordance/ Inadequate e the data have mixed results amongst studies with the highest reliability (i.e., physician-diagnosed asthma with a score of 1 or 2)
Consistency
Dose-Response Limited e no quantitative dose-response information available. Some qualitative information available
Strength Limited - odds ratios were typically moderate, but not strong, suggesting limited strength
Temporality Strong e some longitudinal studies are available
Plausibility Strong e our knowledge of the mechanism of asthma induction and elicitation include irritant and sensitization responses. Some cleaning product
ingredients show these characteristics.
Specificity Limited e there are many causes of asthma and other household (e.g., mold, dander, pollen) and individual susceptibilities (e.g., atopy, exercise) are
predictive of asthma outcomes.

through chemical-induced sensitization or irritation of the respi-
ratory tract. There is, hypothetically, a balance between the use of
cleaning products to reduce mold, mildew, dust, and dander levels
that would not increase the risk of asthma induction or elcitiation
associated with cleaning product use resulting in the minimum
asthma risk.
One goal, in chemical safety assessment, is to identify the
product ingredients that pose the greatest potential to induce or
elicit asthma and seek to decrease their use or promote use of
alternate, inherently safer products. Hazard-based approaches are
intended to decrease the asthma risk associated with cleaning
products. However, use of such approaches on an ingredient-by-
ingredient basis will likely fall short of informing actual risk dur-
ing product use e which requires knowledge of exposure-response
relationships and data on modifying factors (such bioaerosol levels
from cleaning) that impact the overall risk for a specified activity.
 M.J. Vincent et al. / Regulatory Toxicology and Pharmacology 90 (2017) 231e243
Table 6
A summary of the key lines of evidence considered for the acetic acid weight of evidence assessment.
Key Lines of Evidence for Acetic Acid Assessment
End Point Critical Effects Key Studies
Asthma Reactive airways dysfunction syndrome Zuskin et al. (1993, 1997); Shusterman et al. (2003); Ernstgard et al. (2006); Rajan and Davies Human Data:
(RADS) and asthma (1989); Kivity et al. (1994); Amdur (1961)
Sensitization No data No data
Irritant Decreased respiratory rate AIHA (1972); Proctor et al. (1988); Gagnaire et al. (2002); DeCeaurriz et al. (1981)
Overall Weight of Evidence Categorization
A potential next step in the safety and risk assessment process is
to collect data and establish a field experimental protocol that al-
lows for evaluating quantitative exposure response relationships to
chemicals and non-chemical asthma inducers in real world sce-
narios relevant to consumer product uses. Such data can: 1) clarify
the extant significant body of epidemiology by supporting retro-
spective exposure estimates, 2) support improvements to current
exposure modeling tools, 3) move the field of asthma safety and
risk assessment forward by developing an approach for considering
cumulative risks of complex real-life exposures, 4) provide an
additional empirical protocol for safety and risk assessment that
could be added to the suite of tools described in Maier et al. (2015)
for scenarios when exposure data are inadequate for making
effective risk management decisions.
Acknowledgements
This work was sponsored by the American Cleaning Institute,
Washington, D.C. The sponsor group was asked to review the ma-
terial and provide technical comment. However, the results and
conclusions presented represent those of the authors and do not
necessarily reflect the opinions of the sponsors. We wish to thank
Dr. Russell Savage for his editorial review and comments.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.yrtph.2017.09.013.
Transparency document
Transparency document related to this article can be found
online at http://dx.doi.org/10.1016/j.yrtph.2017.09.013.
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