Int. J. Environ. Res. Public Health 20 1 1

, 8

, 2020

- 2073 ; doi :10.3390/ijerph 8 0 62020



### International Journal of

Environmental Research and

Public Health

ISSN 1660

- 4601

www.mdpi.com/journal/ijerph

Review



## Non

- Chemical Stressors and Cumulative Risk Assessment: An Overview

of Current Initiatives and Potential Air Pollutant Interactions

Ari S. Lewis 1

, *

, Sonja N. Sax 1

, Susan C. Wason 2 and Sharan L. Campleman 3

1 Gradient, 20 University Road, Cambridge, MA 02138, USA ; E

- Mail: ssax@gradientcorp.com

2 Department of Environmental Health

, Harvard School of Public Health

, 401 Park Drive, Boston,

MA 02215

, USA ; E

- Mail: swason@ hsph.harvard.edu

3 Electric Power Research Institute, 3420 Hillview Ave

. , Palo Alto, CA 94304

, USA ;

E

- Mail: scampleman@epri.com

* Author to whom correspondence should be addressed; Email: alewis@gradientcorp.com;

Tel.: + 1

- 508

- 224

- 2907 ; Fax: + 1

- 508

- 224

- 2917

.

Received: 24 April 2011 / Accepted: 20 May 2011 / Published: 8 June 2011

Abstract: R egulatory agencies are under increased pressure to consider broader public

health concerns that extend to multiple pollutant exposures, multiple exposure pathways

,

and vulnerable population s

. Specifically

, cumulative risk assessment initiatives have

stressed the importance of considering both chemical and non

- chemical stressors, such as

socioeconomic status (SES) and related psychosocial stress, in evaluating health risks. The

integration of non

- chemical stressors into a cumulative risk assessment frame work has

been largely driven by evidence of health disparities across different segments of society

that may also bear a disproportionate risk from chemical exposures

. This review will

discuss current efforts to advance the field of cumulative risk assessment, highlighting

some of the major challenges

, discussed within the construct of the traditional ri sk

assessment paradigm. Additionally, w e present a summary of studies o f potential

interactions between social stressors and air pollutants on health as an example of current

research t hat support s the incorporation of non

- chemical stressors in to risk assessment. The

results from these studies

, while suggestive of possible interactions, are mixed and

hindered by inconsistent application of social stress indicators. Overall, while there have

been significant advances, further developments across all of the risk assessment stages

( i.e.

, hazard identification, exposure assessment, dose

- response, and risk characterization)

are necessary to provide a scientific basis for regulatory actions and effective community

interventions

, particularly when considering non

- chemical stressors

. A better understanding OPEN ACCESSInt. J. Environ. Res. Public Health 2011

, 8 2021

of the biological underpinnings of social stress on disease and implications for

chemical

- based dose

- response relationship s is needed

. Furthermore, when considering

non

- chemical stressors, an appropriate metric, or series of metrics, for risk characterization

is also needed

. Cumulative risk assessment research will benefit from coordination of

information from several different scientific disciplines, including, for example, toxicology,

epidemiology, nutri tion, neurotoxicology

, and the social sciences.

Keywords: cumulative risk assessment; vulnerable populations; socioeconomic status;

social stress; air pollutants

1

. Introduction

Cumulative risk assessment has existed in some form for many years, such as in the consideration

of multiple chemical exposures, sensitive sub

- populations, and multi

- pathway evaluations in

Superfund risk assessments [ 1 ]

. C umulative risk assessment

, however, has only recently emerged as an

area of interest among regulators and stak eholders concerned about environmental justice as a strategy

for assessing health impacts in underserved communities [ 2

- 5 ]

. As a result

, the focus of risk

assessment is shifting from assessing hypothetical risks to individual high

- impact receptors to

assessing community

- wide population risks. Concurrently, risk assessment as a science is also

undergoing methodological changes. The National Research Council's (NRC) final ― Science and

Decisions ‖ r eport, released in 2009

, recommended several paradigm shifts for advancing risk

assessment, including the need to characterize the effects of multiple stressors, both chemical and

non

- chemical, on public health [ 6 ]

. Specifically, the recommendation was to include all chemical,

biological, physical, and social stressors in cumulative risk efforts.

Despite the inclusion of non

- chemical stressors in the definition of cumulative risk, cumulative ri sk

assessments to date have not included these stressors in a quantitative manner [ 6

, 7 ]

. This is largely

because few traditional toxicological studies are available to support risk evaluations that consider the

combined effects of chemical and non

- chemical stressors

, and suitable epidemiological information is

limited

, as summarized in Section 5 .2

. Additionally, a wealth of information from other disciplines

( e.g

. , psychology, sociology) has yet to be fully integrated into the evaluation of the interactions

between chem ical and non

- chemical stressors and cumulative risk methods for incorporating thes e data

are only now being considered.

Researchers have identified disparities for numerous health outcomes among disadvantaged

populations and hypothesize that exposures to combinations of non

- chemical and chemical stressors

contribute to these disparities ( e.g

. , cancer, asthma, kidney disease, cardiovascular disease, etc. [ 8

- 12 ] )

,

but scientists have an incomplete understanding of the mechanisms by which non

- chemical stressors

alone, or in combination with chemical exposures, contribute to poor health. There is a particular need

to determine whether different chemical and non

- chemical stressors share a common biological

pathway and/or how multiple stressors may modify a chemical dose

- response relationship [ 13 ]

. A

critica l piece in understanding and incorporating the human health risk impacts from non

- chemicalInt. J. Environ. Res. Public Health 2011

, 8 2022

st ressors is the development of an appropriate exposure or dose metric, or series of metrics, for

evaluating these stressors quantitatively

.

Current cumulative risk assessment/impact programs are being developed

, generally focusing on

identifying populations that may have both increased chemical exposure and vulnerability based on a

combination of living conditions or social behaviors ( e.g

. , Cumulative Impacts p rograms in California

and New Jersey). For example, several state agencies have developed a new screening methodology

for identifying areas potentially affected by cumulative chemical and non

- chemical impacts, but the

methodology does not serve as a ― quantitative assessment of communit y health impacts, rather it can

be used as a relative ranking to distinguish higher

- impacted communities from lower

- impacted

communities and to identify which factors are the greatest contributors to cumulative impact ‖ [ 2 ]

.

Thus, there is a need to develop refined methodologies that can operate within a larger framework of

risk

- based decision making, and to use existing tools (either qualitatively or quantitatively) to evaluate

the impacts of these stressors. As suggested by NRC, the effectiveness of cumulative risk assessments

may also be improved by considering what the possible risk management options could be for

reducing the hazard or exposure ( e.g

. , the feasibility of regulation, remediation, education, or other

interventions) in the scoping and planning phase of the risk assessment, rather than at the end, as is

traditionally done [ 6 ]

.

This review will briefly summarize how cumulative risks are currently addressed and discuss

current efforts to advance the field of cumulative risk assessment, highlighting some of the major

challenges, particularly with respect to inclusion of non

- chemical stressors. W e will examine the

importance of considering the biological mechanism(s) underlying associations between chemical and

non

- chemical stressors and h ealth, and efforts to include this information in risk evaluations. The

discussion will focus on the potential interactions that may occur between chemical and n on

- chemical

stressors and their influence on health outcomes

. These concepts are discussed within the construct of

the traditional risk assessment paradigm and applied to the evaluation of both individual and

community risks

. This review is not meant to be an exhaustive analysis of all cumulative risk

assessment efforts, but rather a general overview of key initiatives and research needs

. As part of our

review, and to highlight the type of information that will be necessary to advance the incorporation of

non

- chemical stressors into risk assessment

, we summarize available epidemiological research that

explores the interactions between non

- chemical stressors and air pollutants. Although results from

these studies are mixed, this research provides important insights related to a better understanding of

the cumulative impacts of these stressors. We discuss the findings from these studies as well as

the ir limitations

.

2. What Is C umulative R isk A ssessment ?

As risk science evolves

, the United States Environmental Protection Agency ( US EPA ) has been

asked to consider broader public health concerns that extend to multiple pollutant exposures, multiple

exposure pathways, complex mixtures, and vulnerable population groups. In 2003

, US EPA issued

guidance on cumulative risk asse ssment to formalize this more inclusive approach to risk assessment.

The cumulative risk assessment framework presented by US EPA [ 14 ] defined cumulative risk as ― an

analysis, characterization, and possible quantification of the combined risks to health or theInt. J. Environ. Res. Public Health 2011

, 8 2023

environment from multiple agents or stressors. ‖ Importantly

, US EPA [ 14 ] explicitly underscores the

need for considering both chemical and non

- chemical stressors

, with the latter including (and extend ing

beyond) low income, depressed community property values, limited access to health care, psychosocial

stress, and other stressors not commonly within the purview of US EPA ’ s regulatory framework.

Furthermore

, US EPA's framework represents a shift in the conventional risk assessment paradigm

,

such that assessments would now: ( 1) focus on identifying at

- risk communities as opposed to

hypothetical individual risks for the reasonably maximally exposed individual from point source s or

other environmental or product exposures ; ( 2) use qualitative /semi

- qualitative data ( e.g.

, general

exposure indicators

, severity rankings, non

- quantitative information on known stressor interactions)

,

and ( 3) incorporate non

- chemical stressors. Many of these ideas were further developed, along with

proposed methods for meeting cumulative risk evaluation objectives

, in a 2007 US EPA report called,

― Concepts, Methods

, and Data Sources for Cumulative Risk Assessment of Multiple Chemic als,

Exposures, and Effects: A R esource D ocument ‖ [ 15 ]

. Also, the recent NR C Science and Decisions

r eport reemphasized the need for these shifts and reiterated many of the same cumulative risk

assessment principles [ 6 ]

. The report also highlighted that, to date, consideration of non

- chemical

stressors in the context of background stressors has been limited

.

Some aspects of c umulative risk as sessment have been conducted for decades under the p u rview of

the Comprehensive Environmental Response, Compensation

, and Liability Act (CERCLA) of 1980

,

also known as the Superfund program, which was designed to address risks from multiple pollutants

across multiple pathways for residents living near hazardous waste sites [ 16 ]

. This has mainly been

accomplished through a site investigation to identify chemicals of concern for relevant exposure

pathways and calculating non

- cancer and cancer risks for specific receptor s. CERCLA requires

consideration of "susceptible" receptors as part of the risk assessment process, which generally

includes potentially exposed children, elderly people, or people with p re

- existing health conditions.

This is usually accomplished by identifying the reasonable maximally exposed (RME) individual and

through the application of toxicity criteria that are designed to be protective of the general population,

including sensitive sub

- populations [ 1

, 17 ]

. In general, dose additivity is assumed, both for exposure

pathways and chemicals, although there are provisions to segregate risk by target organ if

appropriate [ 1 ]

. While considering multiple on

- site exposures, risk assessments conducted under

CER C LA or other remediation

- oriented programs do not often take into account non

- point source

chemical exposures ( e.g

. , lead paint) or other community stressors like poor nutrition, obesity, or

presence of psychosocial stress factors when evaluating health risks.

Although the consideration of multi

- chemical, multi

- pathway risks in site

- specific risk assessment

is routine, risk assessments that support the regulation of specific chemicals or processes ( e.g.

, pesticides, food additives, product safety) are usually conducted in isolation, and do not include

background chemical exposures or exposures to additional chemical s or chemical sources

. H uman

studies include individuals (both in the control and chemical

- exposed group s ) who have background

exposures ; as a result, the interaction s between background factors and the exposure s under stu dy are

rarely evaluated in any meaningful way ( i.e.

, findings are usually focused on the chemical exposure)

.

One of the goals of cumulative risk assessment is to address this limitation, and to expand evaluations

to include background conditions (from chemical or non

- chemical stressors) and how they relate to

additional exposure s that could contribute to increased health impacts

.Int. J. Environ. Res. Public Health 2011

, 8 2024

More formal c umulative risk assessments at the agency level are largely focused on chemical

chemical interactions

, likely because information on chemical

- chemical interactions are more data

- rich

than information on chemical

- non

- chemical interactions

. For example, a frequently cited example of

cumulative risk assessment is the evaluation of aggregate exposures to pesticides mandated by the

Food Quality Protection Act of 1996

, which specifically states that pesticides with a common

mechanism of action be evaluated for their cumulative health risks [ 18 ]

. To meet this requirement, a

c umulative risk assessment has been conducted for organoph osphate (OP) pesticides, which i s a class

of pesticides that have a common primary mechanism of action, acetylcholinesterase (AChE)

inhibition [ 19

, 20 ]

. The OP cumulative risk assessment considered multiple OPs simultaneously across

multiple exposure pathways. Based on a common mode

- of

- action (MOA)

, US EPA was able to

assume dose additivity. Currently, a multi

- chemical cumulative risk assessment is in development for

pyrethroid pesticides (type I and type II) [ 21 ]

. U nlike OPs, this group of pesticides does not have a

unified MOA

, and has known interactions with other pesticide classes, which has hindered progress

and highlight s some of the complexities involved in the evaluation of multi

- chemical exposures

, when

additivity cannot be assumed

.

Another example of US EPA's efforts to implement multi

- chemical risk assessment is through the

National Scale Air Toxics Assessment (NAT A) [ 22 ]

. T he goal of this program is to evaluate sources,

levels, and potential risks of hazardous air pollutants (HAPs). By modeling emissions from a variety of

different source types, including major stationary sources, area sources, and on

- road and off

- road

mobile sources, the NATA results provide estimates of airborne exposure concentrations and

associated outdoor inhalation risks for small geographical areas ( i.e.

, at the county and the census

- tract

level). Both cancer and non

- cancer endpoints are evaluated, although non

- cancer endpoints are

restr icted to respiratory and neurological effects. US EPA has made the conservative assumption that

effects of multiple compounds on the respiratory or nervous system will be dose

- additive and

, thus

, a

hazard index for each of the non

- cancer categories is calculated

. To date, three comprehensive

assessments have been conducted based on emission data from 1996, 1999, and 2002 [ 23

- 25 ]

. The

2002 assessment includes emissions, ambient concentration estimates, and exposure estimates for 181

of the Clean Air Act’ s 187 ― air toxics ‖ substances (plus diesel particulate matter).

T hese assessment s

, which are often cited as some of the more robust examples of cumulative risk

assessments

, consider only multiple chemicals and multipl e routes of exposure

, but do not include

consideration of non

- chemical stressors ( inclusion of non

- chemical stressor s may be included in

cumulative risk assessment s

, but are not required under US EPA's definition of cumulative risk )

. I nitial

attempts to achieve the goals of the incorporation o f non

- chemical stressors are only now beginning to

be developed

, particularly in epidemiological research, and preliminary efforts have been successful

in identifying key hazards and exposures, but integration of these components (as is usually

accomplished under the traditional risk methodology) is extremely complex. Some of the complexities

identified in these initial efforts, however, will eventually move the science forward.

3. Vulnerability in the Context of Cumulative Risk Assessment

The integration of non

- chemical stressors in to a cumulative risk assessment framework has been

largely driven by the extensive evidence that there are large disparities in health across differentInt. J. Environ. Res. Public Health 2011

, 8 2025

segments of society [ 9, 26

- 28 ]

. Both US EPA [ 14 ] and NRC [ 6 ] have focus ed discussion of

incorporatin g non

- chemical stressors around the notion of vulnerability. Additionally, the

environmental justice movement, which has been influential in initiating and shaping the direction of

cumulative risk assessment, is premised on the concept that poorer communities are vulnerable both

because they carry a disproportionate amount of the environmental burden and, by virtue of their social

environments, are uniquely sensitive to environmental pollutant expos ures [ 4 ]

.

The consideration of vulnerable or sensitive populations in human health risk assessment is not new.

C onservative inputs in risk assessments are standard practice to ensure protection for the most

sensitive population groups. Risk assessments and health

- based policy have often used terms like

― sensitivity, ‖ ― susceptibility, ‖ and ― vulnerability ‖ interchangeably, often referring to any condition

that increases the probability of an adverse health outcome. In the context of cumulative risk

assessment, the attributes of vulnerability have been more clearly articulated

. Recent literature has

made some distinctions between the different facets of vulnerability, which both US EPA [ 14 ] and

NRC [ 6 ] believe should be considered as a part of the cumulative risk assessment paradigm [ 26 ]

.

In the establishment of National Ambient Air Quality Standards (NAAQS)

, US EPA is mandated

under the Clean Air Act to provide a margin of safety to protect sensitive sub

- p opulations by

considering vulnerability and susceptibility factors in its health assessments. Specifically, Section

109(b) (1) of the Clean Air Act defines a primary standard as ― the attainment and maintenance of

which in the judgment of the Administrator, based on [air quality] criteria and allowing an adequate

margin of safety, are requisite to protect the public health. ‖ Furthermore, the legislative history of

Section 109 indicates that a primary standard is to be set at ― the maximum permissible ambient air

level...which will protect the health of any [sensitive] group of the population, ‖ and that for this

purpose "reference should be made to a representative sample of persons comprising the sensitive

group rather than to a single person in such a group" [ 29 ]

. Table 1 summarizes the vulnerability and

susceptibility factors that US EPA has identified as being associated with specific criteria pollutants. In

general, the NAAQS reports have distinguished between sensitivity ( i.e.

, biological factors, including

age or gender) and vulnerability ( i.e.

, non

- biological factors, such as SES and proximity to roads). This

grouping is similar to the Kasperson scheme highlighted in US EPA ’ s Cumulative Risk Assessment

Framework [ 14 ]

, as discussed below

, but does not overlap completely

— introd ucing some confusion.

This confusion is magnified by the blanket use of the term ― susceptibility ‖ to describe both

susceptibility and vulnerability factors [ 30

, 31 ]

. As discussed in Section 5 .2

, t he lack of a proper

definition and the disjointed way in which these factors are assessed in air pollution studies makes it

difficult to evaluate and use the results in any quantitative fashion. In fact, although this information is

summarized and discussed extensively in the supporting documentation for the NAAQS reviews, it is

not clear how this information is used by US EPA in the establishment the NAAQS.Int. J. Environ. Res. Public Health 2011

, 8 2026

Table 1. Susceptibility and vulnerability factors considered for evaluation of the criteria

air pollutants.

Criteria a ir p ollutant Susceptibility f actors Other v ulnerability f actors Reference

Carbon m onoxide Pre

- existing disease

Age

Gender Differential exposure/dose ( e.g., altitude,

exercise, proximity to roads)

Abuse of medication and

other substances

SES ( e.g.

, education and income) [ 32 ]

Particulate m atter

(PM 10 and PM 2.5 ) Pre

- existing disease

Age

Gender

Genetic factors

Race SES ( e.g.

, education, unemployment,

and income ) [ 31 ]

Ozone Pre

- existing disease

Age

Gender

Race

Genetic factors Differential exposure ( e.g.

, activity level,

time spent outdoors; physical activity)

SES/racial ethnic factors ( e.g.

, education

and income)

Environmental factors (urban vs. rural,

ETV, endotoxin exposure) [ 33 ]

Lead Age

Physiological states

(menopause, pregnancy,

lactation)

Genetic factors

Gender SES ( e.g.

, education, life stress,

and income) [ 34 ]

Sulfur d ioxide Genetic factors

Age SES ( e.g.

, education and income)

Differential exposure ( e.g.

, activity level,

residential location, AC use, time spent

outdoors) [ 35 ]

Nitrogen d ioxide Pre

- existing disease

Age

Gender

Genetic factors SES ( e.g.

, education and income)

Differential exposure ( e.g.

, proximity

to roads) [ 36 ]

Although not developed specifically for cumulative risk assessment, US EPA presented a

framework developed by Kasperson for differentiating among different types of vulnerabilities :

( 1) s usceptibility and sensitivity; ( 2) differential exposure ; ( 3) differential preparedness ; and

( 4) differential ability to recover [ 14 ]

. In terms of human health cumulative risk assessment, it is useful

to think of these vulnerabilit y factors as being related to innate biology or genetics (susceptibility and

sensitivity), disproportionate chemical burden (differential exposure), and social factors (differential

preparedness and recovery). These vulnerabilities may either be related to the individual 's attributes or

may reflect community features that bear on individual outcomes, although some vulnerabilities, such

as socioeconomic status (SES), act on both the individual and community level s

.Int. J. Environ. Res. Public Health 2011

, 8 2027

3.1

. Susceptibility and Sensitivity (Vulnerability Related to Biological Characteristics)

Susceptibility and sensitivity describe innate biological conditions that make an individual or

sub

- population more likely to experience adverse effects from a chemical exposure compared to the

general population

. Susceptibility to environmental insults may be due to life stage ( e.g.

, developing

fetuses, children, the elderly, pregnant women), underlying diseases, and/ or genetics, including

polymorphisms [ 14 ]

.

Traditiona lly, risk assessments have considered these susceptible sub

- populations in development

of q uantitative toxicity criteria , with potential differences in sensitivities among people incorporated

through the application of uncertainty factors [ i.e.

, usually a 10

- fold uncertainty factor (UF) for

i ntraspecies v ariation ]

. According to US EPA [17], ― The intraspecies UF is applied to account

for variations in susceptibility within the human population (interhuman variability) and the

possibility (given a lack of relevant data) that the database available is not representative of the

exposure /dose

- response relationship in the subgroups of the human population that are most sensitive

to the health hazards of the chemical being assessed. ‖ Several studies have evaluat ed the

protectiveness of the 10

- fold UF for interindividual variability [37]

. Based on an evaluation of the

variability in pharmacokinetics and pharmacodynamics within a population, Burin and Saunders [37]

concluded that a 10

- fol d safety factor is protective of greater than 99% of the human population. This

is consistent with conclusions reached by Dourson et al. [38]

, who concluded that, when based on

studies in populations with sensitive individuals, current methodologies are protective for close to 100%

of the general population

. Understanding the biological susceptibilities to disease has been an active area of research for many

years, particularly in the context of early

- life exposures. More recently, researchers have made

advances in understanding the complex interactions between genes and the environment and are

attempting to quantify how underlying existing disease i s influenced by environmental exposures.

These concepts can be incorporated into cumulative risk assessment once they are better developed,

but at present, cumulative risk assessment efforts are more focused on addressing other facets of

vulnerability, inc luding differential exposure and coping mechanisms, as discussed below. While it is

important to understand biological vulnerabilities, and adjustment of chemical toxicity factors may be

warranted, these factors are inherently present within all population s and are thus not subject to risk

management or regulation. Examples of vulnerabilities related to innate biological characteristics, as

well as facets of vulnerability that are more central to current cumulative risk assessment efforts, are

presented in Table 2.

3.2. Differential Exposure (Vulnerability Related to an Increased Chemical Burden)

Vulnerability from differential exposure relates to the concept that an individual or population may

be disproportionately affected by a chemical because of past chemical exposures or increased

contemporaneous exposure that increases the baseline body burd en [14]. D ifferential exposure is

related to the environmental justice movement's concerns that disadvantaged communities are more

likely to experience increased exposure to higher levels of environmental contamination ( e.g. , landfills

and hazardous sites, industry emissions, vehicle emissions, etc. ). Methods for quantifying differentialInt. J. Environ. Res. Public Health 2011

, 8 2028

exposure to multi

- chemical stressors that can be used in cumulative risk assessments are being

developed on multiple fronts, including the use of biomarkers and national da tabases to characterize

chemical exposures. The advantages and limitations of these methodologies are discussed in

Section 4.2.

Table 2. Vulnerabilities related to biological sensitivity, differential exposure, and

differential preparedness and recovery.

Selected potential indicators of

vulnerability (individual) Selected potential indicators of

vulnerability (community)

Susceptibility and sensitivity

(biological characteristics) Inherited diseases/predisposition to disease

Genetic polymorphisms

Age (young/elderly)

Pregnancy/developing fetus

Race/ethnicity/culture

Mental health (coping skills)

Low intelligence

Low birth weight

Differential exposure

(increased chemical burden) Old, substandard housing

Cleanliness/sanitation

Home use of pesticides

Substandard hygiene

Poor ventilation Old, substandard housing

Inadequate air flow

Increased air pollutant exposure

Traffic density

Proximity to hazardous waste sites

Proximity to waste disposal sites

Proximity to industrial releases

Differential preparedness and

recovery

(social environment and

behavior) SES

Family instability

Personal nutrition

Social support

Obesity

Smoking

Drug addiction

Chronic underemployment

Other aspects of psychosocial stress

Health care access

Health behavior s

Reproductive events SES

Crime and violence

Lack of community resources

Crowding

Food supply

Access to quality health care

Substandard schools

Concentration of poverty

Racial segregation

Noise

Civil engagement/political empowerment

Social capital

Sources: [2,26,39,40].

3.3

. Differential Preparedness and Recovery (Vulnerabilities Related to Social Environment and

Behavior)

US EPA [ 14 ] d escribe d differential preparedness as the ability of an individual to withstand the

insult of a chemical stressor based on existing coping systems and resou rces

. Differential preparedness,

therefore, relates to the potential vulnerabilities associated with social environments, including all

aspects of psychosocial stress. Neither US E PA [ 14 ] nor N RC [ 6 ] has pro posed a formal definition ofInt. J. Environ. Res. Public Health 2011

, 8 2029

psychosocial stress, although working definitions have been established by other s

. For example, the

National Institutes of Health (NIH) stated that ―[ p] sychosocial stress refers to acute or chronic events

of psychological or social origin which challenge the homeostatic state of biological systems ‖ [ 41 ]

.

Under this broad definition, psychosocial stress can manifest itself in many forms. These may include

the stress from living near a hazardous waste site or a noisy airport (also a physical stress), as well as

numerous stressors often associated with low SES, such as exposure to violence, unemployment,

and /or an unstable family structure [ 6

, 14

, 4 2

, 43 ]

. Also, differential preparedness might relate to

secondary manifestations of the social environment that increase vulnerability, such as poor nutrition,

substance abuse, obesity, and/or smoking. Preventive health care access can also play an important

role. While it is not feasible to present an exhaustive list of possible factors that contribute

to differential preparedness to a chemical stressor, Table 2 lists examples gathered from several

different publications.

Vulnerability due to differential recovery, described as the ability to recover from the effects of a

stressor [ 14 ]

, is distinct from differential preparedness, but likely depends on many of the same social

factors. Psychosocial stresses, poor nutrition, substance abuse, etc.

, may also affect an individual's or a

community's ability to recover from a chemical exposure. Espe cially important in differential recovery

is health care access. Some of the key stressors associated with differential recovery are also presented

in Table 2

.

As noted above, these types of stresses, in particular, are often viewed as having an impact on the

individual or the community, although overlap occurs ( e.g.

, Personal SES vs. Community SES). This

becomes an important distinction because the relationship between the social stressor and health

outcome for an individual may manifest itself differently at the community level. Also, quantifying the

relationship between disease and individual vs. community stresses, as well as the application of risk

mitigation measures, will likely need to proceed along different lines of research.

4. C umulative R isk A ssessment and the Traditional Risk Assessment Paradigm

As stated earlier, accounting for increased v ulnerability and sensitivity is not new to risk assessment,

but consideration of these issues to date has been mainly accomplished through conservative exposure

assumptions and the application of standard uncertai nty factors to toxicity criteria, a relatively blunt,

but health

- protective approach that has mainly focused on age

- related susceptibilities and the

heterogeneity in a population's response to a chemical exposure

. Moving beyond these conventional

approaches requires consideration of how non

- chemical stressors fit into each stage of the present risk

assessment paradigm

, as proposed by the NRC in 1983 : Hazard Identification

, Dose

- Response

Assessment, Exposure Assessment, and Risk Characterization [ 44

, 45 ]

. Currently, c umulative risk

assessment efforts are community

- level initiatives that use c ommunity information as a basis to build

the risk profile

, mainly in the identification of potential stressors and/or potentially vulnerable

populations groups (see Section 4.4 )

. In contrast, traditional risk assessment s focus more on exposure

sources ( i.e.

, they are source

- centric)

.

To meet the goal of community

- based assessments

, it is important to draw from multiple fields

that have tackled similar issues. For example, s ome researchers have proposed drawing from

ecological risk assessment methodologies, including the use of multi

- level analyses that incorporateInt. J. Environ. Res. Public Health 2011

, 8 2030

individual

- and community

- level effects [ 39

, 46 ]

. The complexity of such analyses can be daunting,

requiring more explicit elucidation of risk assessment goals and coordination of information from

several different scientific disciplines, including

, for example, toxicology, epidemiology, nutrition,

neurotoxicology

, and the social sciences.

At this stage in the development of a cumulative risk framework and methodology, it is unclear if

more research is needed to identify and define non

- chemical stressors such that they can be

incorporated into the existing risk assessment framework or whether a new cumulative risk assessment

paradigm must be developed to accommodate the effects of non

- chemical stressors. In the 2007 US

EPA report, ― Concepts, Methods, and Data Sources for Cumulative Health Risk Assessmen t

, ‖ US EPA

scientists explored new paradigms for evaluating cumulative risks, and

, while aspects of the traditional

risk framework ( i.e.

, the NRC ’ s 1983 risk scheme ) are still central to cumulative risk assessment, US

EPA pr o posed additional steps ( e.g.

, steps involving planning and scoping

, problem formulation, and

supplemental economic, political science, and social analyses ). These additional components represent

an attempt to expand the focus of risk assessments beyond identifying the risk s associated with

sources of contamination to understand all the key potential risks (real or perceived) that a community

may face.

The section below discusses how cumulative risk principles fit into the traditional risk assessment

paradigm, with examples of progress to date and research needs for both community

- based and

individual risk assessment

. While this framework is not sufficient to accomplish all the goals of

cumulative risk assessment, as noted in US EPA [ 15 ]

, it is likely that core elements of the traditional

risk framework will need to be integrated throughout cumulative risk assessment efforts as it develops.

Additionally, we provide a review of current research on how non

- chemical stressors can modify the

health effects of air pollution

, as well as future research needs for application of these data for

cumulative risk assessment

.

4.1

. Hazard Identification

The first stage in risk assessment is identifying environmental agents that are associated with known

health effects. The scientific disciplines of epidemiology and toxicology have been central to this

undertaking, with decades of research being devoted to understanding the link between chemical

exposures and disease on the molecular, cellular, ind ividual, and population level.

The health risks associated with non

- chemical stressors, particularly indicators of low SES, have

been studied extensively, and there is some information to suggest that the biological basis for these

health effects is due to the stress associated with many psychosocial factors ( i.e.

, vulnerability related

to differential preparedness and recovery). Much remains unknown, however, particularly in regards to

the relative contribution from multiple non

- chemical stressors to disease. Importantly, research on the

interaction of chemical and non

- chemical stressors on various health impacts is still in the early stages,

as discussed in more detail below. This may be one reason why neither US EPA [ 14

, 15 ] n or NRC [ 6 ]

has published a list of potential non

- chemical stressors and associated health outcomes that should be

considered in cumulative risk assessments. Instead, non

- chemical stressors have been introduced

inconsistently in peer

- reviewed publications

, often by example

. Many of these are presented in

Table 2

.Int. J. Environ. Res. Public Health 2011

, 8 2031

Much work remains on the identification of potential non

- chemical hazards and their associated

health impacts. As with traditional chemical risk assessments, information from the fields of

toxicology (and other biological sciences) and epidemiology (and other statistic

- based sciences) will

be needed to identify causal links between non

- chemical stressors and disease. In addition, due to the

large number of stressors (both chemical and non

- chemical) that could be considered, methods for

prioritizing or identifying key stressors will be needed to streamline and reduce the complexity of

cumulative risk assessments. The sections below summarize some of the key non

- chemical stressors

that are currently being considered in the context of cumulative risk asses sment efforts.

4.1.1

. Physical and Biological Stressors

In general, non

- chemical stressors are divided into physical, biological, and social factors. Attention

to physical and biological stressors in US EPA [ 14 ] and NRC [ 6 ] reports has been cursory and

lacks clear definition. Physical stressors include radiation, noise, vibration, odor, temperature, and

humidity [ 6

, 14 ]

. Biological stressors largely encompass pathogenic agents ( e.g.

, bacterial and viral agents).

Compared to social stressors (described below), incorporating physical and biological factors in a

cumulative risk paradigm is likely more feasible in the near

- term, mainly because of the availability of

information on biological interactions among stressors, established metrics to evaluate exposure, and

existing risk assessment methodologies for some biological and physical stressors. Also, many of these

stressors are associated with specific health endpoints and even have a well

- defined MOA

, making

them easier to evaluate in the existing risk assessment framework. Yet, integrating this information

into a risk assessment framework has not come to fruition. For example, the scientific literature is

replete with information on radiation (both ionizing and ultraviolet) and chemical interaction s

, which

have been described at the molecular, cellular

, and organism levels. Radiation (ionizing) risk

assessment is particularly well

- developed, and yet, radiological risk s are generally kept separate from

chemical risk assessment, including under the S uperfund program [ 1

, 47 ]

.

Noise

- chemical interactions are also well

- studied, particularly in the context of occupational health.

While there is likely enough information to understand the biological underpinnings of such

interactions, incorporat ion of cumulative effects in a risk assessment framework ha s not been

accomplished [ 48 ]

.

Initiatives to address the intersection of biological and chemical risk have been most robust under

the risk evaluation of biosolids

. W hile there are well

- developed chemical and pathogen risk assessment

methodologies, when NRC evaluated biosolid risk, it concluded that ― because of data gaps and lack of

risk

- assessment methods for complex mixtures, it is not possible at this time to integrate pathogen risk

assessment with chemical risk assessment ‖ [ 49 ]

. Pathogen

- chemical risks have been evaluated in the context of the addition of appropriate

disinfectants to drinking water supplies; however, these assessment s have mainly been evaluated as

risk trade

- offs rather than cumulative impacts. In addition, information applicable to risk assessment

that can be garnered from chemical immunotoxicity studies is available

, particularly studies that

involve pathogen challenges, but, again, implementation of this information in any formal context

remains uncharted.Int. J. Environ. Res. Public Health 2011

, 8 2032

For other physical stressors, such as humidity and temperature, information on the ir relationship

with specific health endpoints is available, but these effects have not been included alongside chemical

exposures in a risk assessment framework. From an exposure standpoint, quantifying these types of

exposure s in a given population is relatively straightforward [ 6 ]

, but more work would be needed to

quantify the effects of the se physi cal stressors on specific disease endpoints. In addition, further

research is needed on potential interactions, i.e.

, whether these are additive (no interaction) or are

capable of exhibiting some elements of synergy or antagonism

.

4.1.2

. Social Stressors

While US EPA and NRC frameworks clear ly state that both non

- chemical and chemical stressors

can be considered in a cumulative risk assessment, this paper will focus on identification,

quantification, and characterization of social stressors specifically

. This emphasis, as discussed earlier,

is consistent with the focus of most cumulative risk programs currently under development

[ e.g.

, California Environmental Protection Agency ’ s (CalEPA) and New Jersey Department of

Environmental Protection's (NJDEP) C umulative I mpacts initiatives]

, where the goal is to identify

populations with greater than average chemical burden (differential exposure) and that are more likely

to experience adverse health effects by virtue of their social conditions (differential preparedness

and recovery).

Psychosocial and related stressors are acute or chronic events of psychological or social origin that

challenge the homeostatic state of biological systems

. Social stressors could also include behaviors

associated with psychosocial stress, such as poor die t, obesity, smoking, and/or illicit drug use. Stress

from living near a pollutant source ( e.g.

, hazardous waste site, power plant, etc. ) has also been

discussed as a psychosocial factor potentially contributing to increased vulnerability to disease.

Several researchers have found it useful to distinguish between social stressors that are primary to

the individual vs. community

- wide social stressors [ 13

, 40 ]

. Although there is overlap, this division is

valuable in the context of cumulative risk assessment, as it can help focus research needs on the factors

that can be evaluated at the individual level vs. those that can be used to assess associations between

stress ors at a population level. Table 2 g roups social stressors affecting the individual and

the community.

Identifying the gamut of possible social stressors is only one half of the equation in the hazard

identification step; the second half involves understanding the relationship between social stressors and

a specific health endpoint. NRC [ 6 ] prop osed two approaches for identifying stressors for inclusion in

a cumulative risk assessment: effects

- based and stressor

- based. The effects

- based approach begins

with an effect of concern, such as elevated respiratory disease or other health problem s of interest in a

population [ 46 ]

. This approach retrospectively uses epidemiological evidence or surveillance data to

identify populations with increased disease, with the objective of understanding the stressors that

contribute to that disease endpoint. Stressors of interest are then identified and assessed both

individually and in combination. Aspects of this approach are borrowed from ecotoxicology, where, in

general, multiple influences, chemical and otherwise, are considered in assessing tot al community

impacts. For example, US EPA has developed a framework for identifying a diverse array of stressors

that may impact water bodies that takes in account information on chemical ( e.g.

, elevatedInt. J. Environ. Res. Public Health 2011

, 8 2033

concentrations of metals or ammonia), physical ( e.g.

, increased sediment or water temperature), and/or

biological ( e.g.

, increased abundance of an invasive species) stressors [ 46

, 50 ]

.

In contrast, the stressor

- based analysis is more prospective and begins with the stressors, then

identifies the populations that may be affected. The concept of this approach is similar to traditional

risk assessment, but in this case would go beyond point

- source exposures and would include

background exposures and non

- chemical information. NRC [ 6 ] s uggest ed that this approach can be

used in conjunction with an assessment of different risk management options to identify a key subset

of stressors of concern and their potential link to health outcomes of interest ( i.e.

, choose only those

that would be affected differentially by the risk management strategies or would otherwise have an

influence on risk estimates). As a simple example, assessment of risk from living near an airport where

air pollution (chemical) and noise (non

- chemical) both potentially affect hypertension, would focus on

reduction of both air pollution and noise if an interaction between the two stressors is associated with

increased risk.

Some researchers have suggested a life

- course approach that incorporates the combined effects of

multiple stressors across a lifetime (from gestation through childhood, up to later adult life) to address

chronic health effects [ 51 ]

. Although the concept may be simple, implementation is complex and

limited to specific knowledge, not only of the physiologic trajectory of normal systems, but also the

impacts of stressors at various life stages. This approach, however, does aid in the organization and

conceptual framework of a complex cumulative assessment.

In response to the difficulty in isolating and testing the social stressor s associated with health effects,

several early attempts at incorporating social stressors into cumulative risk assessment have used

indicators of social stress as a proxy for the actual biological stressors associated with disease. For

example, low SES or poverty is not in and of itself a causal factor for a specific disease, but many of

the attributes of financial instability may influence disease outcomes ( e.g.

, access to health care,

nutritional deficiencies, stress of living in a violent neighborhood). Understanding the biological

mechanisms underlying the ca usality of social conditions

- disease interaction may not be necessary for

preliminary cumulative risk applications, but, ultimately, from the perspective of intervention and

regulatory strategies to improve health, it will be important to have a more precise understanding of

how and to what extent social ― hazards ‖ affect disease incidence. For this reason, the incorporation of

social stressors into cumulative risk assessment is progressing along two fronts

, i.e.

, in assessing risks

at the biological level and in assessing community

- level risks

.

At the community level, researchers have made efforts to identify key demographic variables that

contribute to disease. Much of this research already exists, but draws from scientific disciplines

that are not traditionally associated with chemical risk assessment, such as social science and

psychology [ 52

, 53 ]

. Most of this epidemiology

- based research involves establishing statistical

associations with specific social stresses and specific health endpoints, which is how hazards are

identified. As detailed in S ection 5.2, however

, understanding these associations in the context of

environmental exposures is complex.

Although less well

- developed, there is also research aimed at understanding the biological

responses of social stresses and their relationship with disease. Studying the biology of social stressors

is significantly more complex than evaluating chemical, physical, or biological agents associated with

adverse effects for several reasons. First, social stressors do not exist in isolation; often, different socialInt. J. Environ. Res. Public Health 2011

, 8 2034

stresses are directly correlated and it is difficult to segregate individual stresses to understand disease

relationships. For example, how do we understand the relative contribution of poor nutrition, obesity,

and stress from exposure to violence in an underserved population? Second, many social stressors are

not easily measured in a laboratory setting. Additionally, several stressors in experim ental animals do

not have a clear counterpart in human populations. For example, experimental animals are routinely

confined to small spaces, are often housed singly, and are often denied sex. Thus, results in

experimental animals may not be representative of humans who are not stressed in these ways

. While

animal models have been useful in studying some aspects of social stress ( e.g.

, malnutrition, noise),

they are clearly limited for examining uniquely human conditions, such as the stress of being

unemployed or having poor access to healthcare. The use of animal models to study social stress will

be discussed in more detail in Section 4.3

. Importantly, most of the existing research on the association between social stresses and disease has

not incorporated potential interactions with chemical exposures. Thus, even if a social stress can be

identified as causal in a disease pathway and is considered a ― hazard, ‖ the modifying effects of social

conditions on chemical exposure effects are only now being studied in a limited fashion and much is

still unknown. In Section 5

, we summarize some of the current research on the potential modifying

effects of social indicators on air pollutant

- related health outcomes. This research, which is critical for

the advancement of cumulative risk assessment, will help in developing scientifically sound

community

- based assessments that incorporate biologically relevant stressors

. This will entail

investigation of specific social indicators, specific exposures, and specific health outcomes

. Initial

efforts in this area will be discussed below in the co ntext of air pollution research

.

4.2

. Exposure Assessment

Exposure assessment is the step in the risk assessment process where th e magnitude, duration, and

spatial extent of exposure are defined [ 44 ]

. In traditional risk assessment, which is based on

understanding the incremental risk from chemical exposures, usually from a particular source, little

consideration is given to existing underlying community exposures th at may influence the toxic

threshold of point

- source exposures.

Accounting for existing and incremental exposures (and thereby assessing total body burden) and

the relationship to overall risk is a key goal of cumulative risk assessment. In this context, most work

in cumulative exposure assessment has focused on using geographic information system (GIS)

databases and other general sources of environmental data to identify communities with disproportionate

exposures to environmental contamination [ 54

, 55 ]

. This may include sources of environmental data,

such air pollutant concentrations, which may provide relatively good information about expected

exposures on a community level, but mostly includes indirect i ndicators of potential exposure

. F o r

example, the Toxics Release Inventory (TRI) emissions data, location of hazardous waste sites, the

presence of landfills, national radiation data, and Brownfield development information. Types of

information that are being used as indicators of chemical "over

- burden" are listed in Table 2 and

Table 3.

Much of the current community

- based cumulative exposure assessments focus on consolidating

information on exposure indictors into a central database that can then be used to rank communitiesInt. J. Environ. Res. Public Health 2011

, 8 2035

with potentially high environ mental burdens. On the national level, US EPA’ s Community

- Focused

Exposure and Research Tool (C

- FERST) reflects the most comprehensive effort to integrate publically

available chemical information for use in community

- based cumulative risk assessments. At this time,

this tool is focused on evaluating cumulative chemical exposures, although it has been recognized that

non

- chemical stressors (or indicators of non

- chemical stress

, i.e.

, noise, SES, race, etc. ) should

eventually be incorporated into exposure models [ 55 ]

.

Similar work is being developed by US EPA ’ s Office of Enforcement and Compliance Assurance

(OE C A) (discussed in more detail in S ection 4.4 ). These tools offer a chance to screen for areas with

the potential for environmental contamination, but challenges remain in how to best leverage

community

- level exposure information to understand what factors, and in what proportion, they best

predict individual risk. For example, while the presence of a landfill might be used as an indicator of

the potential for chemical exposures, operational practices and pollution controls vary by facility ;

therefore

, a large amount of uncertainty remains associated with how a specific facility might

(or might not) ultimately impact a nearby community.

A promising alternative approach, which may provide a more direct measure of ― exposure ‖ to

chemical and non

- chemical stressors, is the use of biomonitoring. The potential usefulness of

biomonitoring in a cumulative risk context has been emphasized by US EPA [ 15 ]

. Traditional risk

assessment has used biomonitoring either through the measurement of a single constituent in an

appropriate biological media or through the measurement of disease biomarkers to understand the

relationship between chemical exposure and disease [ 56 ]

. Lead risk assessment is a current example in

which risk determinations and risk interventions are often based on blood lead levels

— a measurement

of cumulative lead exposure from all sources [ 57 ]

. Moving beyond a single

- compound exposure is, of course, central to cumulative risk assessment. In

terms of biomonitoring, measuring the combined exposure of multiple stressors may best be

accomplished through the activation of a common biomarker, such as a biomarker of exposure (with

no direct toxicological consequence), but preferabl y through the activation of a key biological response

involved with the toxicological MOA

. In other words, it would be ideal to identify an early (hopefully

reversible) biological endpoint that becomes activated in response to a diverse set of exposures (both

chemical and non

- chemical).

The idea of examining biomarkers from multi

- chemical exposures is not new. For decades, there

have been attempts to assess total DNA damage by looking at chromosomal damage or DNA add ucts

in workplace environments. In many cases, evaluating a general biomarker of DNA damage was done

in order to identify hazardous industries in which there was limited knowledge of the suite of

chemicals causing adverse effects [58

- 60]. This approach has been particularly prevalent in industries

with exposure to multiple polycyclic aromatic hydrocarbo ns [61].

The lessons learned from biomarker monitoring in the workplace are relevant to cumulative risk

assessment in communities. From a hazard identificati on perspective, understanding how overall

exposures may converge on a precursor to disease may be useful in targeting areas for future study. In

terms of risk characterization, however, it can be difficult to identify the most significant exposures

and des ign interventions when assessing cumulative exposure to multiple chemicals through a

common biomarker.Int. J. Environ. Res. Public Health 2011

, 8 2036

This has been an issue in controlling workplace exposures, but would be even more problematic for

identifying community exposures, where exposures may be diverse in time and space, and may be

associated with multiple sources. Other issues with biomarkers as a measure of exposure include

understanding biomarkers in the context of actual disease incidence

, and the feasibility of collecting

biological samples on a community

- wide scale.

Much of the progress to date in cumulative risk associated with multi

- chemical exposures has

hinged on the idea of different exposures converging on a common biomarker. For example, the risk

assessment of organophosphate (OP) p esticides represents a robust example where a common

biom arker ( a cetylcholinesterase [AChE]) has been used to assess cumulative exposure to distinct

compounds. In the context of OPs, this approach is useful because these pesticides operate via

a common MO A and AChE induction is a key component in the disease pathway to neurological

effects [19,20]

. Using biomarkers to understand how social stressors may contribute to disease will be significantly

more complicated, although biomarkers will likely play an i mportant role in advancing the science. Ideally,

biomarkers will offer an avenue for linking mechanistic

- based research with epidemiological research.

An avenue of research that has been explored in the context of cumulative risk assessment and the

respon se to multiple stressors is the idea of ―allostatic load.‖ Allostasis is the process by which the

body responds to environmental cues to restore homeostasis. The concept of allostatic load was first

introduced by Mc Ewen and Stellar in a 1993 publication, but the concept has been further developed

since then [62 ]

. McEwen [62] u ses the term " allostatic load or overload " to refer to the wear and tear

that results from either too much stress or from inefficient management of allostasis ( i.e

. , not turning

off the response when it is no longer needed )

. Measuring allostatic load, which

, in practice, is

quantifying the exposure associated with stress

, can be done through the measurement of a variety of

different biological functions, including markers of neuroendo crine function ( e.g.

, cortisol and

epinephrine levels), immune function ( e.g.

, Interleukin

- 6, tumor necrosis factor

- alpha) , metabolism

( e.g.

, cholesterol, triglycerides), cardiovascular endpoints ( e.g.

, blood pressure, heart rate), and

anthropometric functions (waste

- to

- hip rat io s, body mass index).

The best indicator of allostatic load, which can serve as a biomarker of psychosocial stress, remains

to be determined. For example, extensive research exploring the relationship betw een measures of

allost atic load and SES and cortisol has gained specific attention as a biomarker for aspects of chronic

stress [63]

. Seeman et al. [64] has reviewed the state

- of

- the

- art information on the link between SES

and allostatic load, noting that, while there is signif icant evidence linking a variety of biological

responses with SES, much more work is needed to understand the biological underpinning of such

responses, the complexity of multiple stress interaction, and the role of genetics. Moreover, t he

combination of i ndicators tha t best predicts interactions between chemical and p s ychosocial stress still

require s further consideration [62].

Allost at ic load may be one way to view how psychosocial stress as an exposure contributes to

disease ; other conditions associated with sub

- optimal social envi ronments will still require further

research ( i.e. , for effects of social elements that are not re lated, the psychosocial stress must be

quantified in a different way). For exampl e, the effects of poor nutrition, drug abuse, and/or access to

health care are separate ― exposures ‖ that are not explicitly captured in an allostatic load model.Int. J. Environ. Res. Public Health 2011

, 8 2037

Appropriate biomarkers that relate to social stresses, but are separate from psychosocial stress, may

need to be developed on a more stress or

- specific basis.

The use of biomarkers to quantify multiple forms of social and chemical stress is promising as a

way to assess risks based on dose

- response to multiple stressors. This is because, in a sense, exposure

is being assessed through a common response. The challenge will be to converge on a response that is

simply indicative of cumulative exposure or a biomarker that is early enough in the disease process to

allow for sufficient intervention to reduce exposures. To our knowledge, there is no re search to date

that has been conducted to quantify cumulative exposures to a given class of environmental pollutants

and social stresses through a common biomarker.

4.3. Dose

- Response

The third step in traditional risk assessment is the dose

- response asse ssment; this step is critical in

quantifying the relationship between the exposure (or ―dose‖) of the chemical(s) of concern and the

health outcome (or ―response‖). In chemical risk assessment, quantifying the dose

- response

relationship is usually the most resource

- and research

- intensive step in the risk assessment process,

but it is a crucial step for quantifying the extent to which a chemical (or non

- chemical) stressor

contributes to disease. Understanding this relationship is necessary for discerning ho w much a

decrease (or increase) in exposure impacts disease incidence. Although the National Academy of

Sciences and US EPA have specifically stated that it is not necessary for cumulative risk assessments

to encompass this quantitative attribute, it is di fficult to imagine how the effectiveness of interventions

could be assessed effectively without a metric for estimating targeted, cumulative risk reduction.

Indeed, US EPA [15] includes quantifying dose

- response relationship as a key step in conducting a

c umulative risk assessment. Because of the complexity in quantifying dose

- response relationships, the

dose

- response assessment is the most underdeveloped part of cumulative risk assessment.

As part of the dose

- response analysis, all relevant scientific dat a ( e.g.

, in vitro studies, animal data,

and human exposure and epidemiological studies) are evaluated to characterize the shape of the

dose

- response, and, if possible, establish an MOA of the agent(s). An MOA analysis will outline the

key steps in a disea se process and help determine the possible form of the dose

- response relationship.

Establishing overlapping and diverging MOAs are an important aspect to cumulative risk assessment,

and have been a central component of the chemical

- only "cumulative risk as sessments" conducted to

date ( e.g. , OP risk assessment). As discussed below, although epidemiological evaluations are useful

for establishing associations, it remains important to understand the biological underpinnings to

definitively establish causal rel ationships between exposure and disease. When examining multiple

exposures, understanding MOA is particularly important to assist in determining whether a given set of

exposures acts independently or whether synergistic or antagonistic relationships exist.

The science of toxic interaction and influence on dose

- response relationship has been accumulating

over the last decade and has mainly been studied in the context of multiple chemical exposures. US

EPA’s ― Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures ‖ [ 65 ]

provides definitions for the different types of chemical interactions ( e.g.

, additive, synergistic,

antagonistic), however these definitions are overly simplistic because the definitions only describe

interactions between two chemicals at specific doses. As such, use of these terms can be misleading, asInt. J. Environ. Res. Public Health 2011

, 8 2038

they often describe an expe rimental outcome, rather than any intrinsic toxicological properties of

the chemicals or stressors [66 ] . In light of this limitation, US EPA has chosen dose

- addition as a

―no

- interaction‖ default for chemical mixtures, defining synergism and antagonism a s more or less

than what would be expected with additivity, respectively. The reason for this limited

- labeling

approach is related to large data gaps in our understanding of interactions; this remains a sizable

challenge. Teuschler [67] presents several re commendations to advance the incorporation of

toxicological data for improved chemical mixture risk assessments, including use of toxicological data

on joint toxic action, statistical methods for analyzing dose

- response for mixtures, and toxicological

and statistical criteria for determining sufficient similarity of complex mixtures. As this science

develops, in theory, these methods could be extended to the consideration of non

- chemical stressors,

allowing for identification of the MOA for relevant non

- che mical stressors and quantification of the

effects that a non

- chemical stressor has on the biological response to a chemical.

A complication of defining the MOAs of non

- chemical stressors ( e.g. , SES) remains their lack of a

biological link to disease, that is, SES itself does not cause illness, but rather certain aspects associated

with SES appear to contribute to disease. Often, it is not possible to isolate the single component of

SES that is coupled to disease, but, as discussed in Sections 4.2 and 5, th ese types of relationships are

being investigated, mainly through correlating non

- chemical stressors with disease biomarkers, and in

epidemiological studies investigating the interactions between non

- chemical and chemical stressors

and disease outcomes, re spectively.

While quantifying chemical dose

- response relationships can often be challenging, quantifying the

relative contribution of chemical and non

- chemical stressors will be more complex. In chemical risk

assessment, characterization for dose

- response relationships usually relies on a combination of animal

and epidemiological data; in cases without supporting human data, it is possible to rely solely on

animal data to quantify the relationship between exposure and adverse health effects. Animal

- based

b ioassays enable the study of dose

- response relationships because study design allows the researcher

to control a number of confounding and modifying factors ( e.g. , age, gender, species, etc. ). Also,

bioassays offer the ability to assess the underlying dise ase mechanisms and serve an important role in

establishing a causal exposure

- to

- disease relationship.

Unfortunately, exploring the relationships between social stresses and disease in animals is not

straightforward, or even possible, because of the large number of social hazards. Certainly, it is not

possible to examine a multi

- faceted human stress factor, such as SES, in bioassays. However, there are

several animal models that can be used to measure the biological consequences of social stress, but

relat ing these results to uniquely human experiences remains problematic. For example, how does a

rodent model examining stress created by exposing a weaker rat to a dominant rat relate to the human

stress of not having a job? Nonetheless, the research that doe s exist on the relationship between social

stresses and biological responses in rodents can be used a basis for understanding stress

- chemical

interactions. Presently, only a limited number of animal studies have simultaneously tested interactions

between e nvironmental chemicals and non

- chemical stressors. For example, several studies have been

conducted in rats to determine the combined effects of lead exposure and stress [68]. These studies are

discussed in greater detail in Section 5.1. It should be noted that while only a limited number of animal

experiments have specifically studied chemical and stress interactions, aspects of animal stress ( e.g.

, lack of sexual contact, small cage size, handling) are a part of most animals studies, such that routineInt. J. Environ. Res. Public Health 2011

, 8 2039

stu dies singularly focused on examining chemical effects are indirectly assessing interactions with

non

- chemical stress as well.

Epidemiological investigations clearly provide a richer and more easily adaptable data set for

assessing quantitative relationshi ps between social stresses and adverse health outcomes. For this

reason, information about the interaction between non

- chemical and chemical stressors has progressed

most rapidly on this front and offers some clear benefits [7]. In fact, Levy [7] has propo sed a

framework for inclusion of the results from epidemiological studies in cumulative risk assessment.

Furthermore, as summarized in Section 5.2, epidemiological studies have begun to consider the effects

of social stressors on air pollution

- related heal th impacts. The potential interaction between

non

- chemical stressors on air pollution effects estimates has been studied for various different health

endpoints, including mortality [related primarily to particulate matter (PM) exposures], neurological

eff ects ( e.g. , related primarily to lead exposures), asthma, and cardiovascular effects. As described in

more detail in Section 5.2, the most frequently evaluated social stressor is some indicator of low SES

( e.g. , low income, low educational attainment, etc. ), but other social stressors, such as exposure to

violence, have also been studied [69].

There is important quantitative information that may be gleaned from existing studies that may help

inform the relative importance of chemical and social factors in the disease process, particularly data

from chemical evaluations applying stratified analys es or quantifying interaction terms with social

stresses. Additionally, there remains a rich body of research defining the relationship between SES and

health that needs be evaluated and adapted to be more compatible with traditional risk assessment. The

e xisting research has helped to establish that interactions likely exist between non

- chemical stressors

and chemicals, but fewer studies have investigated the nature of this interactions ( i.e.

, the magnitude of

this interaction or whether incremental risk from th is diverse array of stressors may exhibit elements of

additivity, synergy

, or even antagonism). Also, although there are attempts to control for confounding,

it is still not entirely possible to separate out all non

- chemical stressors in a study relating environmental

exposures to disease, and

, vice versa, it is equally not feasible to separate out all environmental

influences when studying the effects of a non

- chemical stressor ( e.g.

, SES) on disease. In this sense, it

will be important to unders tand whether any deviations from additivity between a chemical and

non

- chemical stressor have a biological component or are an artifact of study design.

As the science moves forward, it will be important to design studies that allow for more

- refined

measurements of the relative contribution of chemical and non

- chemical stressors to disease.

Understanding relative contributions will be necessary to target the most effective public health

interventions. Facets of social, environmental, and chemical expo sures, however, are dynamic over an

individual's lifetime, and, thus, there is a temporal component to interactions that needs to be

considered [26,40,70].

There are a number of additional challenges to incorporating non

- chemical stressors in dose

- response

evaluations. As noted previously, susceptibility is incorporated into different aspects of the dose

- response

evaluation. A dose

- response relationship not only quantifies the amount of chemical that is required

for an effect, but it is also an expression o f heterogeneity or ―vulnerability‖ in a given population,

where more

- sensitive individuals respond at lower doses. In other words, as a result of our individual

(biological) and population

- specific heterogeneity, responses to chemical exposures exist on a gradient

and form a dose

- response relationship. When heterogeneity related to vulnerabilities is not adequatelyInt. J. Environ. Res. Public Health 2011

, 8 2040

captured in a dose

- response relationship from a single study (and particularly from animal studies),

additional sensitivities can be accounted f or through the use of uncertainty factors. Default assumptions

of linearity or an assumption of no threshold are also meant to be protective of more susceptible

population groups. The more explicit consideration of non

- chemical stressors in cumulative risk

assessment necessitates a re

- evaluation of how heterogeneity is factored into the risk assessment and

whether conventional approaches are appropriate. Care must be taken to not over

- correct for

vulnerability factors that are already accounted for through health

- protective toxicity benchmarks.

4.4. Risk Characterization

Risk characterization is the stage in risk assessment where information from the hazard, exposure,

and dose

- response steps is combined to determine the level of risk. In traditional risk ass essment s

,

decisions about risk level s have relied on quantifying exposures and comparing them to benchmark

toxicity factors. Evaluating multi

- chemical exposures has mainly been accomplished by assuming

chemical additivity for compounds with a common target organ ( i.e. , hazard quotients are added to

produce a hazard index and/or cancer risks are summed).

Recent efforts by US EPA have attempted to refine the methodology for cumulative chemical risk

assessment by examining groups of compounds with overlapping MOAs. For example, as described

earlier, US EPA's cumulative risk assessment of OPs was based on the concept that OPs had a

similar MOA ( i.e. , all acted by inhibiting AChE, but to different degrees). This insight allowed for an

understanding of how dose

- r esponse curves would change under multiple exposures, and, in

conjunction with a comprehensive exposure assessment, US EPA was able to characterize the

multi

- pathway risks associated with multiple OPs [19,20]

. U S EPA has attempted a similar approach

with the pyrethroid risk assessment, but, because it is unclear how the MOAs of different pyrethroids

overlap, establishing combined dose

- response relationships is difficult. The complexities surrounding

pyrethroid risk assessment is an example of the difficult ies that will be encountered in conducting

cumulative risk assessments when considering many different types of chemicals and/or other stressors.

Due to this complexity, there will be a need to understand and integrate information on complex

interactions among stressors through physiologically based pharmacokinetic and pharmacodynamic

(PBPK/PD) research and the construction of biologically based dose

- response models (BBDR). In

theory, BBDR models may offer a way of synthesizing information on multiple resp onses, but from a

practical standpoint, with current technologies, developing PBPK/PD models for a single compound is

research

- and time

- intensive, such that multi

- chemical models, let alone the incorporation of

non

- chemical stressors, will pose significa nt challenges. Some progress, however, is underway. For

example, Wason et al. [71] developed a theoretical risk framework for evaluating cumulative risk to

chemical and non

- chemical stressors, using PBPK/PD models to quantify stressor impacts . They

provided an example analysis with OP risk for an urban low

- income population

, considering the

impact of pyrethroids as a chemical stressor and diet as a non

- chemical stressor on OP internal dose

and AChE inhibition

. This work highlights the utility of comp utational models in cumulative risk

assessment as additional PBPK/PD models are developed. As discussed in Section 4.2, there may be

some opportunity to accomplish integration through the use of biomarkers, but there is still much to

learn about the specific key hazards associated with social stress and the biology behind diseaseInt. J. Environ. Res. Public Health 2011

, 8 2041

causality befor e risk characterization of this nature can move forward. There have been some

rudimentary attempts to characterize the risk of social stress (in the metric of allost atic load). For

example

, Goldstein et al. [72] h a ve developed a computer model to ― predict effects of environmental

and genetic alterations on allostatic load and therefore on the development of multi

- system disorders

and failures .‖ This approach is only conceptual at this point, but may offer a framework for evaluating

the effect of multiple stressors (of different types) on disease progression.

Without a more complete understanding of how dose

- response relationships change when

integrating health outcomes from chemical and non

- chemical stressors, it is difficult to move forward

with the risk characterization in the traditional sense. An early attempt to examine social factors and

the risks from multiple exposure sources is embodied in US EPA ’ s 1992 assessment of Chester, PA,

which is located about 15 miles southwest of Philadelphia [ 73

, 74]. Ch ester has the highest poverty rate

in the state and a large minority population (African American population of 65%). Additionally,

Chester has a high density of waste treatment facilities (sewage, municipal, and medical waste) and

industrial facilities. C hester's high poverty rate, in conjunction with the presence of multiple potential

sources of contamination, eventually led US EPA to conduct an evaluation that included a multi

- route

chemical risk assessment and a survey of health outcomes in the city. Al though based on uncertain

exposure data, the assessment showed that chemical risks were elevated (mainly from nearby facility

emissions and lead exposures). Additionally, several health indictors ( e.g. , specific cancers, total

cancer, total mortality, low birth weight ) were found to be highly elevated compared to the rest of the

state and the country. This first step in examining cumulative risk helped highlight important issues,

but falls short of really understanding the interaction between social factors and environmental

exposures in relation to health outcomes. As discussed earlier, this integration, however, has

significant challenges.

More recent initiatives that seek to quantify the combined effects of chemical exposures and social

stress involve rel ative hazard ranking methodologies ( i.e. , identifying populations that, because of

potentially high chemical exposures and social environment, may be at greater risk of disease).

Understanding how a potential increase in chemical burden and the various soc ial determinants of

disease interact has been an active area of research for years, but tools for characterizing combined

risks and, importantly, for targeting risk reductions, are under

- developed. Presently, proposed

methodologies focus on coarse indicato rs of social well

- being and potential chemical exposures (often

crudely measured by proximity to waste sites or industrial facilities) to provide a way to rank at

- risk

communities. Several of these ranking systems have been proposed for use by federal and state

agencies to meet cumulative risk assessment goals. In general, these ranking systems aim to quantify

what US EPA’s 2007 report [ 15] refers to as initiating factors or population descriptors. The aim is to

identify communities with (1) multiple source s or releases, (2) evidence of elevated concentrations of

pollutants (as measured in environmental media or as biomarkers), and (3) sub

- standard health [15 ]

. Some of the key tools that are in the process of being implemented, and their underlying bases, ar e

discussed below.

One of the first nation

- wide tools used to identify communities with potential disproportionate

chemical exposure and demographic s that may make them more vulnerable to adverse health outcomes

was the Environmental Justice Geographic Assessment Tool. The functionality of this GIS

- based tool

was updated in 2010 and renamed EJView (s ee http://epamap14.epa.gov/ejmap/entry.html ). ThisInt. J. Environ. Res. Public Health 2011

, 8 2042

web

- based resource, available to the general public, will generate maps of areas with information on

toxic releases, water monitoring information, presence of health services, health status, and other

important geographical features. Importantly, this tool simply provides requested information and does

not make any attempt to combine information to gain an understanding of high

- risk areas. However, i n

2006

, OECA unveiled a draft tool called t he Environmental Justice Strategic Enforcem ent Assessment

Tool (EJSEAT). T he stated purpose of the tool is to ― identify areas with potentially disproportionately

high and adverse environmental and public health burden s‖ [75 ]

. Even though the tool was first

introduced over four years ago, the methodology has been neither finalized nor implemented in a

formal decision

- making proces s. The criteria for ranking communities is summarized in Table 3

. In

general, the system relies on publicly available data in four areas: e nvironmental exposures, human

health measures, compliance indicators, and socioeconomic indicators. Although a review of US

EPA ’s methodology is not readily available from the agency, according the National Environmental

Justice Advisory Council ( NEJAC ) w ithin each criteri on

, indicators are normalized to a score between

1 and 100, then the categories are normalized a gain relative to each other and averaged to achieve a

raw score. Ranking is accomplished by normalizing the community

- speci fic raw scores to each other.

The National Exposure Research Laboratory (a division of US EPA ’s O ffice of Research and

D evelopment) has initiated the Cumulative Communities Research Program, which is also developing

a tool to characterize cumulative risk, called Community

- Focused Exposure and Risk Screening Tool

(C

- FERST) [55]

. C

- FERST appears to be similar in concept to EJSEAT, but is intended to provide all

of the backgroun d information necessary for conducting community

- based assessment s

. The goal s of

the tool will be to ― assist communities with the challenge of identifying and prioritizing community

environmental health issues, incorporating the latest research on the science of estimating human

exposure to toxic substances in the environment ‖ [76] and to assess ― exposures and risks in a way that

can be summed across chemical and nonchemical stressors in a comparable manner ‖ [55]

. Acc ording

to US EPA ’s website, this tool is still under development

.

CalEPA and NJDEP are also in the process of developing methods to characterize community risks,

although official guidance is still in draft form [ 2

, 3

, 5 ]

. In principle

, the approaches of both state

agencies are similar (and consistent with US EPA tools), in that relatively rough indicators of both

chemical and non

- chemical stressors are being used to rank communities with the greatest potential for

health risks. In March 2009

, a report to NJDEP from the New Jersey Environmental Justice Advisory

C ouncil (NJEJAC) outlined a methodology for assessing cumulative impacts based on the approach

published by Faber and Krieg, researchers who rank ed communities within Massachusetts on the basis

of environmental bu rden and social factors [ 3 ]

. Later in 2009

, NJDEP published an approach for

moving forward with cumulative risk assessment that included an abbreviated version of the list of

indicators recommended by NJEJAC [ 5 ]

. The approach focused on indicators of environmental burden

and did not address how to consider social element s in the ranking assessment

, although NJ DEP did

find a strong relationship between its indicators of environmen tal exposure and poverty. The indicators

selected by NJDEP are based on existing available data that can be mapped to relatively small

exposure areas (100 square m eters). These indicators are shown in Table 3

.Int. J. Environ. Res. Public Health 2011

, 8 2043

Table 3. Indicators in c urrent t ools to a ssess p otential c umulative r isk in c ommunities

.

Draft CalEPA Cumulative Impacts

Assessment [2] NJDEP Preliminary Screening

Method to Estimate Cumulative

Environmental Impacts [5] NJDEP Strategies for Addressing

Cumulative Im pacts in Environmental

Justice Communities [3] US EPA’ s NJSEAT [75]

Measures of Sensitive Population and Social Indicators

Sensitive Populations None Social Determinants Social Demographic Indicators

% of population under age 5

% of population over age 65 Age of housing

Proportion of population who are children

Proportion of population over age 60

Poverty rate

Median family income

Racial and ethnic composition of population

Unemployment rate

Some measure of parks/recreational space % of population livin g in poverty

% of population counted as minority

% of population 25 years old and

over without a high school diploma

% of population over 65 years of age

% of population under 5 years of age

% of population of limited English

proficiency SES

% Non

- white residents

Median household income

% of residents living below 2X

National Poverty Level

Measures of Environmental Exposure Burden

Exposures Exposures Pollution burden Environmental indictors

PM 2.5 concentrations NATA cancer risk Lead in blood of children age 6 or younger NATA cancer risk

Ozone concentrations NATA diesel exposure RCRA sites NATA non

- cancer risk

Releases from industrial facilities (TRI Estimated benzene emissions TRI NATA non

- cancer diesel PM

data) Traffic (all) US EPA National Priorities List sites Toxic chemical emissions and

Traffic (trucks) Power plants transfers from industrial facilities

Density of major regulated sites Treatment, storage, and disposal facilities Population

- weighted ozone

Density of known contaminated sites Brownfields monitoring data

Density of dry cleaners Known contaminated sites Population

- weighted PM 2.5 Density of junkyards Municipal incinerators monitoring data

Resource recovery landfills

Incinerator ash landfills

Dry cleaners

Sewage treatment plants

Ga soline stations

Municipal solid waste landfills

Trash transfer stationsInt. J. Environ. Res. Public Health 2011

, 8 2044

Table 3. Con t

.

Environmental effects Compliance indicators

Hazardous waste and cleanup sites Inspections of major facilities

Leaking underground fuel tanks Violations at major facilities

Formal actions at major facilities

Facility density based on all facilities

in US EPA ’ s facility registry system

Measures of Existing Public Health Problems

Public health Existing health problems Human health indictors

Low birth weight Total cancer incidence rate % infant mortality

Cancer mortality rate Total cancer death date % low birth weight births

Asthma hospitalization rate Asthma: hospitalization rate

Asthma: emergency department visits

Chronic lower respiratory disease

Carbon monoxide poisonings

All

- cause mortality rate

Coronary heart disease rate

Low birth weight rate

Infant mortality rate

Birth defect rate

Some measure of violence/crime

Other

Availability of preventive services

Childhood lead screening rate

Other?

Basic information

Total population of census tract

Size (area) of census tract

NATA = National Air Toxics Assessments; RCRA = Resource Conservation and Recovery Act; TRI = Toxic Release Inventory.Int. J. Environ. Res. Public Health 2011

, 8 2045

In August 2010

, CalEPA released a draft report called ― Cumulative Impacts: Building a Scientific

Foundation ‖ [ 2 ]

. As shown in Table 3

, CalEPA has divided potential indicators of cumulative risk into

five categories: e xposure, e nvironmental e ffects, p ublic h ealth e ffects

, s ensitive p opulation s

, and SES

factors. The indictors in each category are provided by way of example and do not represent an

exhaustive list of potential indicators. Consistent with other ranking approaches, CalEPA intends to

combine these variable s to screen (or rank) communities with the highest potential for cumulative risk

impacts. Specially, the categories are grouped as being related to either ― Pollution Burden ‖ or

― Population Characteristics

. ‖ Within each of the groups

, the categories are given a score (each

category has a specific range). Next, the total score for ― Pollution Burden ‖ is multiplied by the total

score for ― Sensitive Population. ‖ Sco r es can range from 6 to 120, and

, by this met hod, communities

are ranked. In general, CalEPA note d that this approach will help identity communities with the

potential to have the highest risk burdens so that these communities may be targeted for various

risk

- mitigating activ ities such as permitting, remediation, enforcement, and environmental monitoring.

CalEPA also note d that this information can be used for risk assessment and standard

- setting

, although

details on how this information would be used has not been fully developed.

In these approaches

, only direct measures of exposure (instances with actual exposure point

concentrations being measured or modeled ) are chemical concentrations in air. This is not surprising

,

due to the existence of relatively extensive national (NATA) or regional ( California Air Resource

Board) databases for air contaminants and the infrastructure for mapping air contaminants to specific

locations. From this perspective, understanding cumulative air impacts, at least in terms of

chemical

- chemical exposures, is more developed than understanding cumulative risks from chemicals

in other media ( e.g.

, water, soil). The measures of other forms of environmental contamination

applicable to cumulative exposure remain unexplored and hypothetical. For example, as discussed in

Section 4.2

, it is not clear how the density of dry cleaners or living near a hazardous waste site relates

to actual exposure and consequent risk.

An example where NATA data were considered in a cumulative risk assessment framework is the

community case study conducted b y Fox et al. [ 77 ] of neighborhoods in Philadelphia. Specifically, the

researchers used publically available informatio n on hazardous air pollutant concentrations ( i.e.

, US

EPA NATA data) combined with toxicologically available information ( e.g.

, the US EPA Cumulative

Exposure Toxicity Database) to calculate a hazard index as well as a hazard ratio (based on

LOAEL/NOAEL toxicity information) at the census

- tract level, assuming additivity across HAPs. The

researchers also compiled neighborhood age

- adjusted cause

- specific mortality statistics years potential

life lost (YPLL) rates (total, cardio vascular, and respiratory). Fox et al. [ 77 ] assessed potential

associations between mortality and YPLL rates and HAPs risk ratios for both White and non

- White

populations using both nonparametric ranking statistics as well as regression analyses. In the

regression analys e s, the authors also controlled for income. The authors found that compared to

national averages the study neighborhoods had higher mortality rates and cumulative health risks

across Whites and non

- White populations. The correlations results suggested that there was a weak

correlation between hazard ratios (based on the NOAELs/LOAELs) and mortality and YPLL rates,

particularly in the non

- White populations. These associations were significant only for total and

respiratory mortality/YPL L, and not for cardiovascular endpoints. The authors caution that the results

do not imply causality. While this case study represents a step forward in cumulative risk assessment,Int. J. Environ. Res. Public Health 2011

, 8 2046

socioeconomic variables included in the study ( e.g.

, racial composition and income) were limited and

as acknowledged by the authors, they were not fully incorporated in the risk analyses, they were

merely used as potential confounders in the regression analysis, and to test for effect modification in

the ranking analysis.

Using a different approach, Su et al. [ 78 ] developed a Cumulative Environmental Hazard Inequality

Index (CEHII) as a means of incorporating both chemical hazards and socioeconomic characteristics to

asses cumulative environmental impacts. The authors used this index to assess impacts in Los Angeles

County, CA. Cumulative exposures to three different pollutants were evaluated, including NO 2 (as a

marker of traffic

- related air pollution), PM 2.5 (as a marker of a secondary air pollutant with longer

residence time), and cancer risks from diesel emissions. The social indicators used included

racial

- ethnic composition (% of population that is non

- White) and income level (% of population with

income 200% below federal poverty level). Cumulative risks from air pollutant exposures were

assessed by both a population

- weighted multiplicative and an additive approach. The combined effects

of social disadvantage and cumulative air pollutant risk were assessed by calculating the CEHII, where

this index provides a measure of the unequal distribution of the cumulative air pollution risks by

census tract in order to rank

, in a quantitative way, potential vulnerable communities ( e.g.

, because of

lower SES) that are also at greater health risks from multiple chemical exposures. This method,

however, does not integrate the social indicators into the risk calculation in the traditional risk

assessment way; therefore the question remains whether these communities are at increased risk

because of interactions between SES status and cumulative environmental hazard index or whether

these are independent risk factors

. Therefore, while useful in identifying hazards and the relative

contributions from several chemical exposures, the combined effects on actual health status in these

communities remains elusive.

The approaches described above represent the first attempts to implement the basic principles of

cumulative risk assessment

. H owever, while these tools may be useful for identifying communities that

may potentially be exposed to high levels of contamination, they are not sufficient to quantitatively

characterize risk in those communities to combined effects of chemical and non

- chemical stressors or

to understand the relative contributions to risk of social stressors and chemica l exposures. In fact,

many of the criteria being identified through these programs are consistent with the initial key step

( e.g.

, identification of initiating factors and population descriptors) proposed by US EPA [ 15 ] for

conducting a cumulative risk assessment. In other words, the programs proposed by CalEPA and

NJDEP may help prioritize the communities where risk assessments are needed, but, this can only be

viewed as an initial step, with the more rigorous risk characterization step still in its infancy

. I f the goal

is to identify vulnerable populations and quantify chemical risk, the ranking approach may offer an

important first step, but if US EPA wants to expand the process to assess risks from multiple chemical

to one that fully incorporates non

- chemical stressors, more research, methodologies, and guidance will

be needed. T here is a particular need to apply dose

- response concepts to the combined exposures to

chemical mixtures and non

- chemical stressors in a way that will make these risk ranking programs

more useful.

Although all leading environmental agencies are explicit that cumulative risk assessment can be

qualitative, a failure to root out the relative contribution of chemical and non

- chemical stressors in the

quantitative context may hinder efforts to move assessment s that are inclusive of these social stressorsInt. J. Environ. Res. Public Health 2011

, 8 2047

forward. Under the traditional risk assessment methodology, if information on non

- chemical stressors

is only qualitatively characterized, the risk assessment process stalls at the hazard identification stage,

and, because a dose

- response is not established, it will not be possible to determine if interventions that

limit specific environmental exposures will have an impact on public health.

4.5

. Risk Management

Usually risk management is not part the traditional risk assessment methodology; however, the

management

- based risk assessment is one of the stated hallmarks of cumulative risk assessment [ 6 ]

.

Other than focusing on vulnerable communities, it is unclear how these rankings systems will translate

into regulations that will improve public health. California's Cumulative Impacts report provides some

indication of planned activities in response to identifying cumulative hazards, including a more

- refined

permitting process for the release of toxic substances, focused remediation projects, and other activities

aimed at reducing the environmental burden in vulnerable communities. What remains unresolved,

however, is the feasibility of mitigating disease in socially dis advantaged communities, primarily

through the control of environmental exposures. With new risk assessment tools, we can identify the

general exposures and social conditions that may make a community more vulnerable, but without

knowing how and to what extent these factors interact to cause disease, it will be difficult to design the

most effective intervention.

The identification of the relative contributions of chemical and non

- chemical stressors to disease in

cumulative risk assessment offers the opportunity to consider public health more holistically such that

interventions may not need to be restricted to reducing environmental exposures. Indeed, we may be

able to use information from cumulative risk assessments to design policies that target the stressors

(chemical or not) that contribute most to disease burden. For example, if research were able to

understand the relative contribution of PM 10 vs. density of community health centers to cardiovascular

disease, it would allow for better

- informed decisions about where to allocate resources. Of course, not

all social stressors are amenable to intervention, so in the spirit of cumulative risk assessment, which is

chartered to be management

- based, it may be useful to focus on social stressors that can be controlled

on some level, either through regulation or community initiatives.

An advantage of including social stressors in the list of possible stressors that can be controlled is

that, because social stressors are multi

- faceted, reducing social stress associated with a specific disease

will likely benefit other elements in the social environment. To follow the example above, increasing

the number of community health centers, which would have a larger impact on reducing cardiovascular

diseases than further PM reductions, would likely lead to a reduction in other health endpoints as well.

Analysis of chemical and social environment interactions with disease will need to draw on research

in toxicology and epidemiology, but also from expertise in the other fields

, such as sociology and

psychology. There is a great deal of existing research that, while not specifically aimed at informing

cumulative risk assessment, will be helpful in shaping the paths forward. Importantly, as discussed in

the next section, the role of epidemiological research in cumulative risk assessment is promising.Int. J. Environ. Res. Public Health 2011

, 8 2048

5. Non

- Chemical Stressors and Air Pollution Exposures

In the preceding sections, cumulative risk assessment concepts were discussed within the traditional

risk asse ssment framework and some of the major challenges associated with conducting cumulative

risk assessments using existing approaches were identified. A s discussed, a significant missing piece in

these preliminary efforts has been quantification of dose

- response for cumulative effects. As part of the

dose

- response evaluation, both animal studies and epidemiological studies are typically considered;

however, limited information is currently available to help inform the combined effects of chemical

and non

- chemical stressors, and most of the research is not in a form that makes it amenable to

quantify ing dose

- response interactions. Nonetheless, this research serves as an important foundation

for future studies. The following sections summarize some of the available research from animal and

epidemiological studies that have evaluated the modifying effects of non

- chemical stressors on

chemical effects. This summary is not meant to be an exhaustive review of the literature, but reflects

much of the current research, which has primarily been conducted on air pollutants and on markers of

lead exposure ( e.g.

, blood lead and bone lead measures).

5.1

. Animal Studies Examining the Cumulative Effects of Exposure to Chemical and Non

- Chemical

Stressors

Our literatu re search uncovered only a limited number of animal studies that have evaluated the

interaction between chemical and non

- chemical stressors. For example, several studies have been

conducted on rats to determine the combined effects of lead exposure (only via the oral route) and

stress (as reviewed by Cory

- Sletcha et al. [ 68 ] ). In these studies, the authors assessed changes to the

hypothalamic

–

pituitary

– adrenal (HPA) axis

, the system that coordinates the body's physiological

response to stress, in the offspring of female rats that were exposed to lead and stress, both alone and

in combination. The HPA axis effects were measured via corticosterone (the rat equivalent of cortisol)

and neurotransmitter levels; behavioral effects were also evaluated. Two types of stress were used:

restraint stress and cold stress. Significant effects were reported for stress and lead independently, and

for the combined exposures. However, these results were significant only for some of the tested

exposure time points; thus, effects were dependent on the developmental period of exposure, the

timing of the measurement, the behavioral baseline, and gender. Because results were not consistent

across study parameters, conclusions are difficult to draw from these studies; the findings, however,

suggest that the combined effects of lead and stress are greater in female rats, compared to male rats. In

addition, under certain study conditions, no effects of lead alone were observed, only in combination

with stress, indicative of a potential potentiated effect of the combined exposure to stress and lead.

In another study of lead exposure, Schneider et al. [ 79 ] reported that rats raised in an impoverished

environment and exposed to lead via drinking water had spatial learning deficits and decreased

neurotrophic factor gene expression in the hippocampus. Rats raised in an enriched environment, in

contrast, had little to no neurological deficits associated with lead exposure. The authors hypothesized

that impoverished environment s may exacerbate the neurotoxicity of lead, or

, alternatively

, an

enriched environment may counter these effects. Similar results were reported by Guilarte et al. [ 80 ]

,

where spatial learning deficits, as well as decreased levels of neurotransmitters and nerve growthInt. J. Environ. Res. Public Health 2011

, 8 2049

factors, associated with lead exposure in rats

, were reversed in animals that were reared in an

enriched environment.

In a more recent study, Clougherty et al. [ 81 ] assessed th e modifying effects of chronic social stress

on the respiratory response to concentrated fine particles. A rat model of social stress, which involves

introducing animals into the cage with a dominant male, was used as a stressor. The results suggested

more severe lung function deficits associated with fine particle exposure in stressed animals compared

to non

- stressed animals. However, the authors caution ed that the study was limited by the small sample

size. In addition, the authors point ed out that an important challenge in conducting animal studies of

this kind is distinguishing between effects from acute stress and chronic stress, which have distinct

physiological attributes in rats. For example, the acute stress associated with removing the animal from

the cage to conduct the experiments may actually yield attenuated effects, or mask some of the chronic

effects of stress.

Clearly, research in this area is in its infancy. While complicated, this research, as well as

supporting studies that focus on the mechanistic underpinnings of responses, is important to advance

our understanding of how the biology of non

- chemical stressors and chemical stressors intersect and

modify dose

- response relationships.

5.2

. Epidemiological Studies Examining the Cumulative Effects of Exposure to Air Pollutants and

Non

- Chemical Str essors

Air pollution epidemiological studies have begun to consider the effects of social stressors on air

pollution

- related health impacts. Table 4 presents some of the key studies that have evaluated social

stressors in conjunction with air pollutants. The potential interaction between non

- chemical stressors

and air pollution effects has been studied for various different health endpoints, including mortality

(related primarily to PM exposures), neurological effects ( e.g.

, related primarily to lead exposures),

asthma, and cardiovascular effects. The most frequently evaluated social stressor is a measure of low

SES ( e.g.

, low income, low education al attainment, etc. ), but other social stressors, such as exposure to

violence, have also been studied [ 69 ]

. There is currently no consensus on the best indicator of social

stress. Different studies use different indicators, and most often these are measures of education,

occupation, and income, or some combination of these factors. Although related, they represent

different dimensions of SES [ 82 ]

. In addition, SES indicators are often measured at different

geographic resolutions ( i.e.

, at the individual, community, or city/county level). This may explain some

of the inconsistent findings across studies tha t have evaluated the effects of SES on air pollution health

impacts, as discussed below.Int. J. Environ. Res. Public Health 2011

, 8 2050

Table 4. Studies of effect modification of social stresses on chemical health impacts.

Health outcome Chemical stressor Non

- chemical stressor Results Reference

Mortality

Short

- term studies CoH (PM indicator); SO 2 SES indicators: unemployment,

poverty, education, high

manufacturing employment Effect modification by SES measures;

slightly higher relative risks and more

significant results across the lag periods

tested [89]

PM 2.5 SES indicators: household income,

poverty, education Effect modification only significant for

household income [90]

PM 10 adjusted for O 3 , SO 2 , NO 2 , CO SES indicators: education, annual

income No effect modification by SES [91]

PM 10 SES indicator: education Evidence of weak effect modification by

education [87]

PM 10 SES indicators: unemployment,

poverty level, education No effect modification by SES [92]

PM 10 , O 3 SES indicator: sociospatial

development index (based on homes

with electricity, homes with piped

water and drainage, literacy, and

indigenous language speakers) PM 10 not associated with mortality;

ozone was significantly associated with

mortality, but no consistent effect

modificatio n observed [93]

PM 10 SES indicators: education, income,

living in slums Effect of PM on respiratory mortality

was negatively correlated with % college

education, % family income > $3,500,

living in slums [94]

PM 10 SES indicator: composite index Larger effect in higher SES areas but not

statistically significant [95]

TSP, CO, NO 2 , SO 2 , O 3 , PM 10 , CoH,

PM 10

- 2.5 SES indicator: income Only NO 2 was associated with mortality

in low income groups [96]Int. J. Environ. Res. Public Health 2011

, 8 2051

Table 4. Cont.

Health outcome Chemical stressor Non

- chemical stressor Results Reference

Short

- term studies PM 10 SES indicator: education Larger mortality risk estimates were

observed in least

- educated for all cause,

respiratory, and heart disease

- related

mortality [97]

PM 10 SES indicator: income, index that

includes education, occupation,

unemployment rate, family size,

crowding, home ownership The PM 10 - mortality association was

greater in lower income and lower SES

communities [98]

O 3 SES indicator: education, income,

unemployment, poverty Effect modification only for

unemployment; higher mortality rates for

higher unemployment [99]

Long

- term studies PM 2.5 , sulfates SES indicator: education Significant effects for both PM 2.5 and

sulfates in least educated [84]

PM 2.5 , sulfates SES indicator: education Patterns are similar to previous study but

effect modification is less clear; for

ischemic heart disease pattern was

reverse (most educated has greatest risk) [85]

TSP, BS, NO 2 SES indicator: education No effect modification by educa tional

attainment [100]

BS SES indicator: education No effect modification by educational

attainment [101]

TSP, SO 2 SES indicator: income Relative risks were higher for the low

household income category [102]

Air pollution index: sum of

standardized measures of TSP and

SO 2 Deprivation index (includes

unemployment and education) No effect modification [103]Int. J. Environ. Res. Public Health 2011

, 8 2052

Table 4. Cont.

Health outcome Chemical stressor Non

- chemical stressor Results Reference

Neurological effects Blood lead SES indicator: income Cognitive deficits (Kaufman

Assessment Battery) associated with

neonatal blood lead only in poorer

families [104]

Blood lead SES indicator: income No modifying effect of SES on blood

lead

- learning/IQ association, but

observed trend of greater vulnerabil ity

in lower SES subgroup [105]

Blood lead SES indicator: parents' occupational

prestige Modifying effects by SES were

observed for IQ and blood lead, but

interaction became non significant when

adjusted for other factors (age at testing,

iron status, birth weight, etc. ) [106]

Blood lead SES indicator: composite index

including education and father's

occupation Effect modification of lead

- related

decreased performance in visual

- motor

integration and choice reaction tests [107]

Blood lead SES indicators: Hollingshead ’ s

Four

- Factor Index of Social Class, a

measure of parents ’ occupational and

educational achievements Modifying effects by SES were

observed for Mental Development

Index and blood lead only at ages 18 to

24 months [108]

Bone lea d SES indicators: neighborhood

psychosocial hazards (neighborhood

violent crimes, 911 calls, etc. ) Psychosocial stress exacerbated effects

of lead on 3 of 7 cognitive measures [109]

Cardiovascular Disease Lead (bone lead) SES indicators: stress (based on

standardized questionnaire and self

reported) Effects of lead on hypertension were

more pronounced in stressed individuals [110]

O 3 , CO, NO 2 SES indicators: education, income No effect modification by SES on

cardiac hospital admissions [111]Int. J. Environ. Res. Public Health 2011

, 8 2053

Table 4. Cont.

Health outcome Chemical stressor Non

- chemical stressor Results Reference

Asthma and other

respiratory diseases NO 2 (proxy for traffic) SES indicators: exposure to violence Elevated risk of developing asthma with

increased NO 2 exposure only in children

with higher exposure to violence [69]

Traffic

- related air pollution

(Nitrogen Oxides) SES indicators: parental education,

parental stress High parental stress was associated with

higher incidence of traffic

- related risk of

developing asthma. An increased risk of

asthma was also observed for low SES

families exposed to air pollution [112]

O 3, SO 2 , NO 2 SES indicators: education, income Greater hospitalizations for respiratory

effects in lower education and lower

income strata [113]

NO 2 , SO 2 , O 3 , CO SES indicator: average household

income adjusted for household size Male children had higher asthma

hospitalizations in low SES group with

exposure to NO 2 ; female children had

higher asthma hospitalizations for SO 2 in

the low

- income group. No associations for

O 3 or CO [114]

NO 2 SES indicator: insurance status Children without insurance had higher risk

of asthma admissions than those with

private insurance [115]

PM 10 , O 3 , sulfates, strong acidity SES indicator: insurance status The overall hospital admissions association

for both O 3 and PM 10 was driven by the

uninsured minority population [116]

NO 2 Life stress Greater inflammatory markers associated

with high stress in low pollution exposure

group [117]

CoH = coefficient of haze; SO 2 = sulfur dioxide; PM 10 = particulate matter > 10 μm; O 3 = ozone; NO 2 = nitrogen dioxide; CO = carbon monoxide;

TSP = total suspended particulate matterInt. J. Environ. Res. Public Health 2011

, 8 2054

Indictors of low SES have traditionally been treated as confounders in epidemiological

investigations [ 83

- 85 ] ). The definition of a confounder is a variable that is associated with both the

exposure and the outcome, but is not on the exposure

- disease causal pathway. Therefore, in a sense,

factors such SES have been accounted for, but often not as a causal disease agent. However,

researchers have begun to explore whether aspects of SES are actually effect modifiers of air

pollution

- related health effects [ 86

, 87]

. An effect modifier is a factor that results in a change in the

magnitude of an association between an exposure and an outcome when data are stratified by that

factor [88]. By stratifying the analysis by non

- chemical stressors, researchers can gain a better

understanding of their influence and the magnitude of the modifying effect.

There is no clear consensus on how to treat social stressors in epidemiological studies, whether as

confounders or effect modifiers, and the answer may be that it depends on the stressor and how it is

defined and measured. Care must be taken in epidemiological studies to test stressors, particularly for

confounding, as biased estimates will result if confounding is not properly accounted for. This is one

of the most challenging and complicating aspects of current epidemiological efforts to incorporate

non

- chemical stressors. These challenges have been explored most extensively with regard to the

combined effects of social environment and neurological deficits as sociated with lead exposure and the

association between mortality and PM exposure

, as discussed below.

5.2.1. Mortality

A significant disparity in mortality rates exists among populations of different SES, both for all

- cause

mortality and for specific causes of death, such as cardiovascular disease and cance r [118,119].

Moreover, several researchers have suggested that air pollution contributes to the observed disparities

in specific health effects (e.g., asthma or cardiovasc ular disease), leading to premature death. The two

suggested hypotheses relate to the vulnerability factors discussed earlier, namely: ( 1) differential

exposures ( i.e. , low SES populations are differentially exposed to air pollution); and ( 2) differential

preparedness/recovery or coping ( i.e. , low SES populations are more vulnerable to the effects of air

pollution due to, for example, poor health, psychosocial stress, or nutritional status). Most of the

existing air pollution research has focused on underst anding vulnerability related to the biological

susceptibilities associated air pollution ( e.g. , pre

- existing disease, age, and sex) [120

- 122], b ut, in

support of environmental justice concerns, research has shifted to also consider social condition

vulnera bilities [26]

. A large majority of studies that have evaluated the potential modifying effects of non

- chemical

stressors have focused on mortality outcomes in relation to short

- term and long

- term exposures to air

pollutants. The results from these studies, which all evaluated different indicators of SES ( typically

educational attainment or income), have been inconsistent, making it difficult to draw any conclusions

(Table 4).

5.2.1.1

. Short

- term S tudies

Short

- term mortality studies have not found consistent effect modification when analyses included

stratification by SES. For example, no or weak modifying effects were observed in several largeInt. J. Environ. Res. Public Health 2011

, 8 2055

US

- based studies that examined the modifying effects of SES indicators on PM 10 mortality [87,91,92]

.

Simi larly, in a study of residents of Mexico City (>65 years of age), O ’ Neill et al. [93] reported that

ozone

- related (O 3 ) mortality risks did not show any consistent trends of effect modification when

stratified by SES indicators. In addition, two studies conducted in São Paulo, Brazil reported

contradictory results. Martins et al. [94] reported that respiratory mortality for PM 10 was negatively

correlated with percent college education and percent family income (>$3,500), and also reported a

non

- significant positive correlation with percentage of people living in slums.

In contrast, Gouveia and Fletcher [95] found greater PM 10

- associated mortality risks in districts

with higher SES for residents in São Paulo, Brazil, although the results were not statistically significant.

Jerrett et al. [89] found slightly higher relative risks across lag periods, both for mortality risks

associated with coefficients of haze (CoH, a PM indicator) and for sulfur dioxide (SO 2 ) in lower SES

areas of Hamilton, Canada compared to higher SES areas. However, relative risks were not greatly

elevated compared to the overall regional estimates ( e.g.

, regional CoH multi

- lag mortality RR

= 1.06,

whereas low SES RR

= 1.08). Villeneuve et al. [ 96 ] also reported an increased percent in mortality

associated with NO 2 in a study in Vancouver, Canada for low

- and middle

- income families (overall

percentage increase

= 3.5% with 1 day lag per 17.5 parts per billion increase in NO 2 , increased to

about 10%). Total suspended solid

- related (TSP) mortality also increased with stratification by income

levels, but similar increases were observed across all income strata. The authors stated that results

should be interpreted with caution due to the small number of deaths in the income strata. No mortality

effects were reported for other criteria pollutants.

In a PM 10 study of residents in 20 US cities, Zeka et al. [ 97 ] found a slightly elevated percent

increase risk of mortality for non

- trauma mortality (0.62%, 95% CI 0.29

– 0.95) in a cohort of

less

- educated residents (<8 years of schooling) compared to more educated residents (>12 years

schooling, 0.27%, 95%

− 0.004

– 0.54), although the trend was not significant. Similar results were

observed for cardiac disease mortality, but not other causes of death ( e.g.

, respiratory, stroke, etc. ). In a

study in Rome

, Italy that used both income and an SES index (which included census data on

education, occupation, unemployment rates, family size, crowding, and residence ownership)

, the

authors reported higher PM 10

- related all

- cause mortality for lower income and lower SES communities

(1.9% and 1.4% per 10 μg / m 3 increase in PM 10 , respectively) compared to an overall mortality increase

of 1.1% per 10 μg / m 3 for all residents [ 97 ]

. Lastly, in a more recent study, Franklin et al. [ 90 ] assessed

the modifying effects of various community

- level socioeconomic variables (median household income,

percent of population below poverty line, percent of adult population having graduated high school) on

the mortality risks associated with PM 2.5

. Of these variables, only household income had a significant

effect on the mortality estimates (specific results not reported by the authors). Similarly, for ozone

related mortality, a modifying effect was reported for community

- level unemployment rates (with

higher risks associated with higher unemployment) in 98 US urban communities

, but not for other SES

indicators

, such as education, income

, and poverty [ 98 ]

.

Given the large variability in air pollutants evaluated, together with the diverse SES variables

included in the short

- term studies, it is difficult to draw conclusions from these studies. Furthermore,

results do not support a definitive modifying effect of SES on mortality related to air pollutants

, underscoring the need for more research in this area.Int. J. Environ. Res. Public Health 2011

, 8 2056

5.2.1. 2

. Long

- term S tudies

Two seminal US studies [the Harvard Six Cities study and the American Cancer Society (ACS)

study] have found consistently elevated mortality associations with long

- term PM exposures. These

studies, and in particular the ACS cohort, have been the subject of extensive analysis and follow

- up

and have had a large influence on formulating regulation for PM 2.5 since the PM 2.5 standards were

establishment in 1997 [ 31

, 84

, 123

- 126 ]

. The most recent re

- analysis and follow

- up studies of the ACS

cohort have also provided some important insight into the question of the influence of SES and other

factors on air pollutant related mortality estimates. In 2000

, results were published on the re

- analysis

of Harvard Six Cities Study and the ACS of particulate air pollution associations with mortality

to address potential biases in risk results as well as the robustness of the results to model

specification [ 84 ]

. As part of extensive sensitivity analysis of the ACS cohort, the authors tested

confounding and effect modification for a number of sociodemographic and environmental variables

including several SES factors ( e.g., education, income, poverty and unemployment). The results from

these analyses indicated that there was no confounding effect of these ecological factors [ 84 ]

. As the

analysis re lied on multi

- level data [ individual

- level and metropolitan statistical area ( MSA )

- level

covariates ] in a two

- stage random effects Cox model, the authors speculated that the extensive number

of individual

- level variables included in the first stage may have removed possible confounding effects

before the ecologic covariates were tested in the second stage.

In addition, as part of the sensitivity analysis, Krewski et al. [ 84 ] identified potentially ― susceptible ‖

subgroups and conducted analyses stratifying by potential modifying factors. The only modifying

factor that was found to have a significant effect was education, which was chosen as a surrogate of

SES. In the ACS cohort, Krewski et al. [ 84 ] found that cardiovascular mortality was significantly

associated with both PM 2.5 and sulfates among the least

- educated. For all

- cause mortality, the RRs

were 1.35 (95% CI: 1.17

– 1.56) and 1.27 (95% CI: 1.13

– 1.42) in the <high school education groups for

PM 2.5 and sulfates, respectively. For cardiovascular mortality, the effects in the <high school educated

were 1.47 (95% CI: 1.21

– 1.78) and 1.39 (1.20

– 1.62) for PM 2.5 and sulfates, respectively. These effects

were larger than the effects reported for the complete cohorts. The difference in the relative risks may

be indicative of the additional risks associated with some component of SES.

Conflicting results were reported in the recent extended analysis of the ACS c oho r t [ 85 ]

. This

analysis extends the follow

- up time to 18 years ( 1982

– 2000 ). As in the previous analyses, the current

evaluation featured sensitivity analyses that address potential confounding effects of ecologic

vari a bles (such as education attainment, housing characteristics, and level of income) on the air

pollution

– mortality association, but these variables were examined at both the Zip Code area (ZCA)

scale, the MSA scale, and by the difference between each ZCA value and the MSA value

, whereas in

the previous analyses only the MSA level was evaluated. The results from this follow

- up showed

increased mortality risks with the inclusion of SES indicators in the model. For example, the strongest

associations with all

- cause mortali ty was reported with inclusion of the household income variable,

with mortality hazard ratios of 1.048 (95% CI: 1.030

– 1.068) compared to the unadjusted ratio of

1.034 (95% CI: 1. 1016

– 1.053). In the previous analysis, income had no effect on mortality risk

estimates [ 84 ]

. The source of the discrepancy between the results from the previous analysis and the

follow

- up analysis is unclear. Although in this recent analysis the authors used a finer unit ofInt. J. Environ. Res. Public Health 2011

, 8 2057

aggregation (ZCA vs. MSA), they also found that when they compared models that utilized different

geographic units of aggregation (ZCA, MSA, etc. ) there was no appreciable difference in the hazard

ratio estimates [ 85 ]

. The follow

- up also assessed effect modification by education finding that for this

follow

- up cohort, a trend of effect modification by education was more difficult to discern and that for

some health outcomes ( e.g.

, ischemic heart disease), there was a reverse trend such that greater risks

were observed for the more educated. As these results suggest

, there is a need to more clearly define

the role that indicators of SES play in confounding or modifying associations between health impacts

and air pollution exposures.

The modifying effects of education were also examined in a French study [ 99 ]

. In this study, the

authors looked at all

- cause mortality associated with long

- term exposures to TSP, black smoke (BS)

,

and NO 2 , finding no significant trends in mortality effects as a function of education. Similarly,

education did not appear to modify the relationship between mortality and BS in a Dutch study by

Hoek et al

. [ 100 ]

.

Two long

- term Canadian studies also evaluated the modifying effects of SES indicators on

long

- term air pollution exposures. Finkelstein et al. [ 101 ] r eported statistically significant mortality

associated with TSP exposures in both low

- and high

- income groups, with larger effects in the

low

- income group (RR

= 1.14, 95% CI: 1.07

– 1.20 vs. 1.04, 95% CI: 1.10

– 1.06). Mortality associated

with SO 2 exposures were significant only in the low

- income group (1.18, 95% CI: 1.11

– 1.26). In the

second study, the authors investigated the modifying effects of a deprivation index on cardiovascular

mortality related to both TSP and SO 2 (assessed as an air pollution index), finding no significant

interactions [ 102 ]

.

Laurent et al. [ 127 ] revi ewed these and other epidemiological studies of the interaction between

SES and air pollution

- related mortality. The authors were not able to make formal comparisons

between studies due to the large variety of SES indicators used across the studies. One important

finding was that no effect modification by SES was found in studies that used SES indicators at coarse

geographic resolutions (city or county level), whereas mixed results were reported for studies that used

SES measures at finer geographic resolutions ; most studies (5 out of 6) that had individual

- level SES

measurements found evidence of greater mortality risks in disadvantaged individuals. The authors

stated that there is not enough information to conclude that SES modifies the relationship between air

pollution and mortality outcomes.

5.2.1. 3

. Car diovascular Effects

Fewer studies have examined the interactions between social stressors and air pollution

- related

cardiovascular e ffects (other than mortality)

. In one cross

- sectional study of 513 people with

hypertension and 237 without hypertension, Peters et al. [ 109 ] ev aluated the how stress modified the

effects of lead exposure (measured by bone lead levels) on hypertension. Stress was measured using

the Health and Social Behavior questionnaire

, as well as measures of self

- reported stress. The authors

reported that the effects of lead on hypertension were more pronounced in highly stressed individuals.

Results were robust to inclusion of several confounders including age, body mass index

, family history

of heart disease

, education, smoking, alcohol consumption, physical activity, and nutritional factors.Int. J. Environ. Res. Public Health 2011

, 8 2058

In another study, Cakmak et al. [ 110 ] a nalyzed the interaction of SES factors with gaseous air

pollutant

- related cardiac hospital admission s in 10 large Canadian cities using time

- series analyses

adjusted for day of the week, temperature, barometric pressure, and relative humidity. The authors

found that exposure to O 3 , CO

, and NO 2 were individually statistically significantly correlated with

cardiac hospital admissions, with even larger combined effects. The air pollution

- related cardiac

effects, however, were not modified by consideration of gender or community

- level indicators of SES

(namely education and income). The authors concluded that the community

- level indicators of SES

used in the study did not identify potential susceptibility.

Several studies have looked at the correlation between cardiovascular risk factors (obesity,

hypertension, smoking, and physical inactivity) and individual (educational attainment) and

community

- level (unemployment rate and overcrowding) SES indicators. A study conducted in

Germany and the Czech Republic [ 128 ] reported that smoking was significantly correlated with areas

with the highest unemployment rates in both countries, even with adjustment by individual SES factors

.

In Germany, obesity and low physical activity were also statistically significantly associated with

community

- level SES indicators after adjustment for individual SES factors. Interestingly, these

effects are similar in magnitude to the cardiovascular health effects observed in air pollution studies

(see, for example, US EPA [ 31 ] ).

As with the mortality studies, epidemiological evidence of an interaction between air pollutant

exposures, social stressors

, and health is limited and inconsistent. Therefore, more research is needed

to help clarify whether interactions exist, as well as the type of interaction and the potential magnitude.

5.2.1. 4

. Neurological Effects

Controlling for confounding factors in epidemiological studies is complex and requires an

understanding of all important cofactors that that can distort the true relationship between a chemical

exposure and a given outcome. If the cofactor is a truly independent predictor of outcome, it can be

adjusted for using standard statistical techniques. In some cases, however, the chemical and some

cofactor may be so highly correlated that it is difficult to disentangle it using these standard

statistical methodologies.

The complexities of the relationships between chemical exposures and the social environment

have been studied extensively in the epidemiological research related to lead exposures and

neurodevelopment. Several studies that have reported declines in test scores per unit increase in lead

biomarkers have also observed a large reduction in these neurological impacts when adjusting for

indicators of the social environment. For example, i n early studies of lead effects on IQ, no effects

were observed when social factors were accounted for in regression analyses [ 129

, 130 ]

. Also, Tong

and Lu [ 131 ] reported that adjustment for quality of home environment, SES, maternal intelligence,

and parental smoking reduced the association between lead and intelligence quotient (IQ) by up to

40%. Similarly, in a pooled analysis of seven prospective studies, the association between lead and

childhood IQ was reduced from

− 4.66 (95% CI:

− 5.76 to

− 3.60) to

− 2.70 (95% CI:

− 3.74 to

− 1.66),

when variables for study site, quality of home environment, birth weight, maternal IQ, and maternal

educa tion were included in the model [ 132 ]

. In fact, some researchers have determined that blood lead

may account for only 1

– 4% of the variability in child IQ scores, compared to about 40% or more forInt. J. Environ. Res. Public Health 2011

, 8 2059

social and parental factors [ 133 ]

. More recently, researchers have questioned the adjustment of lead

effect estimates by SES factors as overly conservative and have suggested instead that SES indicators

are more likely to modify the association between lead and cognitive deficits [ 105

, 134 ]

. For example,

researchers point to the health effects associated with elevated glucocorticoids (a marker of chronic

stress), which are also elevated with lead exposures and can affect behavioral processes. Thus, an

important question is whether there is an interaction between risk factors associated with lead exposure

and those associated with environmental stress, and whether these effects are synergistic. There is

currently only suggestive evidence of an interaction from both animal and human epidemiological

studies. In addition, SES can contribute to higher exposures of lead due to living conditions ( i.e.

, older

housing) and inadequate healthcare, thus contributing to additional vulnerabilities from differential

exposure and differential preparedness.

Cognitive deficits in children (measured using the Kaufman Assessment Battery) were reported to

be associated with neonatal blood lead concentrations in a Cincinnati cohort of four

- year

- olds, but only

for children from poorer families [ 35, 103 ]

. In a f ollow

- up on the Cincinnati study Ris et al. [ 104 ]

reported that SES was not a significant modifier of the higher blood lead (taken at age 78 months)

associat ion with lower learning/IQ scores, but they observed a trend of greater vulnerability in lower

SES adolescents exposed to higher lead levels

. This trend is supported by a study i n an Australian

cohort of children

, in which c ognitive deficits were reported to be more prevalent in lower SES

groups [ 105 ]

. Tong et al. [ 105 ] stu died 375 children in South Australia prospectively from birth until

11

– 13 years old. The researchers evaluated the interaction between blood lead levels and

sociodemographic factors [gender, parents' occupational prestige (measure of SES), quality of the

home, and maternal IQ] on children's IQ. The authors reported statistically significant interaction with

gender ( i.e.

, girls were more sensitive) and with SES measure, but these effects were reduced and

became non

- significant when adjusted for other covariates ( e.g.

, age at testing, grade in school, iron

status, birth weight, feeding method as infant, marital status of parents, etc. ).

Three cross

- sectional studies in Europe among preschool and school

- age children found that

increased lead exposure resulted in decreased IQ and decreased performance in visual

- motor

integration and choice reaction tests, but only in children of low SES [ 106 ]

. In a similar study

conducted in the US, the correlation between the Mental Development Index (MDI) and cord

- blood

lead levels were evaluated for infants at ages 6, 12, 18, and 24 months of age [ 107 ] stratified by social

class. Social class was measure d based on Hollingshead's Four

- Factor Index of Social Class, which

includes a measure of parents' occupational and educational achievements. The results showed that, at

ages 6 and 12 months, there was no significant difference of effect of cord

- blood lead on MDI acro ss

social status, but, at ages 18 and 24 months, differences in the relationship between blood lead levels

and MDI were significant

, but only at the low and medium lead exposure levels

. In th e infants in

the high blood exposure level category, however, the differences in MDI performance were

indistinguishable between social status category.

Bellinger et al. [ 107 ] a lso found that results varied depending on the age at which child was

exposed to lead

. For example, w hen blood lead levels were taken at 6 months of age, declines in MDI

score with increased blood lead concentration were observed only in the lower SES group. No trends

were observed when analyses were conducted using blood lead levels taken at 12, 18, and 24 months

of age. The authors thus theorize d that vulnerability to lead toxicity is dependent on both the infants’Int. J. Environ. Res. Public Health 2011

, 8 2060

SES and age. It is worth noting that the authors found that the interaction between lead exposure and

SES did not show evidence of additivity or multiplicativity in these older age groups. In other words,

children with the worst values on both factors ( i.e.

, highest lead exposure and lowest social stratum)

did not display the worst performance, as may be expected with a synergistic effect. For example, in

this study, the children with the highest cord

- blood lead levels had similar MDI scores regardless of

social status. The authors also state d that interactions between risk factors should be interpreted with

caution due to sample size considerations. These studies highlight much of the uncertainty and

limitations associated with relying solely on epidemiological studies for use in cumulative

risk assessments.

Although most studies have focused on the effects of lead exposures in children, one recent study in

adults found that psychosocial stress modifies the effects of lead on cognitive function in adults.

Glass et al. [ 108 ] assessed how neighborhood psychosocial hazards, measured independently from

subjects using neighborhood information on violent crimes, 911 calls, etc.

, as a measure of a

― heightened state of vigilance, alarm and threat, ‖ may modify the effects of lead (bone

- lead

measurements) on cognitive function in adults aged 50

– 70 years old. The study, which was conducted

in Baltimore, Maryland, showed that psychosocial stress exacerbated the effects of lead on three out of

seven cognitive measures after adjusting for potential confounders (age, sex, race, education,

technician, time of day)

— namely, language, processing speed, and executive functi oning.

Overall, both confounding by SES and effect modification have been reported in epidemiological

studies of lead exposure and neurological deficits, primarily in studies of children

, and more recently

in adults. These studies provide some of the strongest evidence of potential effect modificat ion by SES

factors, but inconsistencies have been reported that underscore s the need for further research.

5.2.1. 5

. Asthma and Other Respiratory Health Effects

A growing area of research is in understanding the large disparities in asthma morbidity. The ex c ess

asthma morbidity and mortality observed in inner

- city, lower

- income, and ethnic minority

communities in not well

- understood, and the relative importance of the urban environment, lower SES,

or ethnicity as independent risk factors remains controversial [ 27 ]

. Current research on the modifying

effects of non

- chemical stressors on air pollution

- related effects indicate that there is a potential

interaction. For example, Clougher ty et al. [ 69 ] asses sed the potential modifying effects of exposure to

violence (ETV) as a measure of a chronic social stressor on traffic

- related asthma etiology. The

authors used novel GIS methods to retrospectively estimate traffic

- related air pollution exposures

(using NO 2 as a surrogate) for 413 children in a pregnancy cohort. Air pollution estimates were

analyzed in conjunction with questionnaire

- based data on ETV to assess development of asthma in the

cohort. The authors found no independent effect of ETV on asthma (OR

= 0.98, 95% CI: 0.78

– 1.22),

but an elevated risk of asthma was found with increased NO 2 exposures only in children that had

higher ETV

, indicating greater air pollution susceptibility. For example, in the cohort of lifetime

residents, the effects of NO 2 on asthma were positive and almost significant ( odds ratio ( OR )

= 1.28,

95% CI: 0.97

– 1.69), but in the stratified cohort, NO 2 was significantly associated with asthma among

children with above

- median ETV (OR

= 2.33, 95% CI: 1.47

– 3.71), but not the children with

below

- median ETV ( OR

= 0.87, 95% CI: 0.59

– 1.28). Similar results were obtained when the analysesInt. J. Environ. Res. Public Health 2011

, 8 2061

included potential confounders ( e.g.

, maternal asthma, exposure to tobacco smoke, education, sex, and

age). The authors noted the difficulties in interpreting the interactions between air pollution exposures

and non

- chemical stressors, such as ETV, because behaviors among people living in violent

neighborhoods may differ from those living in less violent areas, such as keeping children indoors

,

where they may be exposed to greater NO 2 levels from indoor sources ( e.g.

, smoking and gas stoves)

or to other indoor pollutants ( e.g.

, indoor allergens). In addition, ETV may be a proxy for other social

stressors, such as family instability.

In another study of asthma, Shankardass et al. [ 111 ] evaluated effect modification by low SES

(using parental education) or high parental stress (measured by way of a questionnaire) on

traffic

- related asthma etiology. Approximately 2,500 children (ages 5

– 9) with no history of asthma or

wheezing were followed for three years. Exposure to traffic

- related air pollution was determined using

dispersion modeling. High parental stress was associated with higher incidence of traffic

- related risk of

developing asthma. An increased risk of asthma was also observed for low SES families exposed to

air pollution.

I n contrast to the findings in the studies describe d above, in which the interaction of the

non

- chemical stressor with the chemical stressor appear to act in combination to increase asthma, a

study that evaluated the modifying effects of life stress (assessed via interviews) on NO 2

- related

inflammatory markers and asthma symptoms, reported greater inflammatory markers associated with

greater stress at lower air pollution exposures, no t higher air pollution [ 116 ]

. The authors theorized that

their findings may be related to a threshold effect in which the chronic stressor (in this case stress)

lowers the threshold such that adverse effects occur at lower pollutant exposures. The authors also

suggest that the differences observed in this study compared to previous studies may be related to the

focus on children with existing asthma vs. the onset of asthma, an d that different social stressors may

have a differential effect on asthma exacerbations.

In a study conducted in 10 large Canadian cities, living in communities in which individuals have

lower household education and income levels was associated with greater hospitalization for

respiratory health effects, indicating that these individuals may have increased vulnerability to air

pollution [ 112 ]

. Stratification by education yielded significant increases in hospitalizations for the

lowest educational attainment strata (<Grade 9) for O 3 and SO 2 , but not NO 2 ; the percent increase was

not significantly different from the unstratified risk values. For example, for O 3 , the unstratified risk

was 3.8% (95% CI: 1.9

– 5.6) and for <Grade 9, the risk was 4.0% (95% CI: 1.6

– 6.5). Similarly, the

combined effects of all three gaseous pollutants yielded the greatest percent change in hospital

admissions in both the unstratified and the stratified models (6.6%, 95% CI: 3.5

– 9.7 and 7.0%, 95% CI:

2.5

– 11.5, respectively). Significant risk of hospitalization stratified by income were found for O 3 and

NO 2

. The risks for NO 2 for the lowest income level (<$21,309) were higher than the unstrat i fied risks

(5.1%, 95% CI: 1.6

– 8.8 vs. 2.5%, 95% CI: 0.2

– 4.8), as was the multi

- pollutant effect (8.6%, 95% CI:

4.3

– 12.9). In a similar study of asthma hospitalizations in children ( ages 6

– 12 ) in Vancouver, Canada,

greater risks from asthma hospitalizations in male children of low SES were observed with exposures

to NO 2 , compared to male children in the higher SES group (OR

= 1.13, 95% CI: 1.04

– 1.23 vs.

RR

= 1.04, 95% CI: 0.95

– 1.14 at lag

= 1 day); in female children, significant asthma hospitalizations

were found for SO 2 only at lags

= 4, 5, and 6 days [ 113 ].Int. J. Environ. Res. Public Health 2011

, 8 2062

Disproportionate asthma hospitalizations were also observed in a study in Phoenix, Arizona using

insurance status as an indicator of SES. Grineski et al. [ 114 ] reported that children without insurance

had a 1.4 times higher risk of asthma hospital admissions

, compared to those with private insurance

with a 0.02 parts per million (ppm) increase in NO 2 above the seasonal mean. Insurance status was also

found to significantly modify the effect of ozone and PM 10

- related respiratory hospital admissions i n

New York City. After adjusting for insurance status, significant relative risks of hospitalization were

reported in the uninsured subgroups, but not in the insured subgroups. In fact, these results also showed

that the air pollution

- hospital admission association was largely driven by the uninsured population.

The modifying effects of SES on air pollution

- related respiratory morbidity are suggestive of an

effects at this point

, but questions remain as to the nature of the modifying effect, i.e.

, whether these

effects are additive, synergistic, etc. In addition, because

, as with other epidemiological studies

, these

studies used varying indicators of SES or social stress ( e.g.

, education, exposure to violence, and

insurance status)

, it is difficult to compare results across studies.

5.2.1. 6

. Limitations A ssociated with the U se of E pidemiological D ata

The epidemiological research to date has contributed to a better understanding of potential

interactions between social stressors and air pollution exposures, but more research is needed to

confirm the results and resolve some of the inconsistencies across studies. Limitations and issues

associated with using epidemiological results include biase d effect estimates, exposure errors, and

assuming causality when biological mechanism s of low

- dose exposure effects are not well understood.

R esolving these issues will be an important step in the current risk ranking efforts so that the best

indicators of social conditions are being used to identify the communities at risk. In the absence of this

analysis, cumulative risk ranking programs may be incorrectly targeting communities for further analysis.

After clearer associations are established for specific indicators of social stress with specific chemicals

and for specific endpoints, it will be possible to develop more specific risk mitigation measures.

As mentioned previously, epidemiological studies examining gross measures of disease are not

likely, in and of themselves, to provide refined estimates of the relative contribution of chemical and

non

- chemical stressors to disease. It is therefore important to consider multiple lines of evidence

(animal, cellular, and molecular studies) to determine which data will be most informative in

elucidating MOA

, as well as dose

- response information. Research is moving towards trying to better

understand the interactions between environmental exposures and non

- chemical stressors

. Similarly, as

mentioned previously, studies of allostatic load (including methods for measuring allostatic load) and

the effects of multiple stressors offer some promis e for identifying potential MO As [ 62

, 1 35 ]

. Lastly,

"molecular epidemiology" methods, which incorporate biological events at the physiologic, cellular,

and molecular levels, and thus enhance the biological understanding of epidemiological findings, may

prove to be useful in cumulative risk assessments.

6. Research Needs and Conclu s ions

The application of cumulative risk assessment to include the incorpor ation of non

- chemical

stressors to address environmental justice concerns requires improved or new method ologies that can

be applied at the risk characterization stage of the risk assessment

. Examples of robust cumulative riskInt. J. Environ. Res. Public Health 2011

, 8 2063

assessments are available, but generally do not include assessment of non

- chemical stressors in any

quantitative way. In addition, a majority of environmental applications of cumulative assessments have

focused on evaluating health effects associated with air pollutants, with or without consideration of

population level indicators for other stressors ( e.g.

, census level demographics, SES, etc. ), primarily

due to the relative availability of geographically based air pollutant data and basic health surveillance

data ( e.g.

, population level mortality or cancer data). Other metrics of exposure via other media are

also being explored. In these studies, r isk

- ranking methods, correlating high incidence of disease with

potential chemical exposures (measured often crudely by proximity to pollution sources) are typical in

these assessments and are descriptive in nature

. These descr iptive applications serve communities by

providing indicators of exposures and in identifying risk distributions across communities, and, in

doing so, help to identify environmental health disparities and potentially vulnerable population groups

( e.g.

, with the reliance on GIS methods). In this respect, these qualitative assessments remain

important. Epidemiological research has progressed in the evaluation of the modifying effects of social

stressors on chemical exposure

- related health impacts, albeit with mixed results. This research

however, offers not only a way to better understand potential interactions, but to potential quantify

their effects. As with more routine single

- chemical risk assessments

, there is a substantial challeng e in

linking dose

- response information gleaned from animal and in vitro studies with epidemiological

observations. These challenges are more pronounced in cumulative risk assessment

, where both the

underlying biology and exposure assessment are more complex, particular ly when non

- chemical

stressors are involved.

C hallenges remain in the effort to include non

- chemical stressors in the cumulative risk assessment

framework in order to obtain a useful environmental and public health analysis and evaluation tool.

T he present inability to fully quantify risks using comparative metric(s) capable of accounting for

non

- chemical stressors makes it difficult to assess cumulative impacts consistently across different

populations, locations, or time periods. This inability to compare risks quantit atively, which is

necessary for designing and evaluating environmental health intervention programs or for assessing the

effectiveness of environmental regulation, continues to impair the application of cumulative risk

assessment inclusive of non

- chemical stressors

. In addition, to communicate intervention strategies and

regulatory initiatives to any affected communities

, fair and clear interpretation of risks and competing

uncertainties is necessary

. T o advance the incorporation o f non

- chemical stressors into risk

assessment s in a manner that will facilitate effective public health interventions

, research in the

following key areas is needed:

 Identification of the elements of low SES that have the most significant impact on disease

( e.g.

, to what relative extent does poor nutrition vs. psychosocial stress vs. lack of quality

healthcare play a role in disease), investigated on a disease

- specific basis.

 Metrics to describe degrees of psychosocial stress and other key biological effects of

non

- chemical stressors, specifically expressing non

- chemicals stressors in manner where

― dose ‖

- response relationships can be explored.

 Correlations between gross measures of exposure ( e.g.

, the presence of a landfill) and actual

chemical exposure in a population.Int. J. Environ. Res. Public Health 2011

, 8 2064

 Biomarkers that are reliable indicators of the cumulative effects of chemical and

non

- chemical stresses.

 Correlations between stress induced in animals and psychosocial stress in humans,

specifically whether these animal stress models are applicable to human conditions.

 Quantification of the interactions between non

- chemical stressors and chemicals and their

relative role in health outcomes. Specifically, how dose

- response curves change with

combined exposures to chemical and non

- chemical stressors.

 Epidemiological evaluations specifically designed to explore the relative contribution of

chemicals and non

- chemical stressors in disease outcomes, and

, specifically

, how

observations relate to dose

- response relationships.

 Focused efforts to better ― link ‖ research on dose

- response relationships to observations

gleaned from epidemiological evaluations.

While much new research is necessary, it should be emphasized that there is a wealth of information

to draw on from disciplines not usually associated with chemical risk assessment.

Acknowledgements

This work was sponsored by the Electric Power Research Institute. We would like to thank Ruth

Buchman, Jasmine Lai

, and Anna Engel for their help in editing and preparing the manuscript.

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