The life course theory is one that can be used to understand the factors that affect lead exposure risks and disease outcomes. It can be defined in this context as a study of long-term “biological, behavioral, and psychosocial processes that link adult health and disease risk to physical or social exposures acting during gestation, childhood, adolescence, earlier in adult life or across generations” [1
]. The theory states that developmental processes such as delayed development or environmental conditions in utero, which are averse to proper growth and development, are associated with an increased risk of middle and later life illnesses [1
In the model, there is a belief that many of the chronic and adverse health outcomes are created early in development in utero and then bring forth lasting damage to the adult later on. The theory also speaks of damaging physical and social environments which create pathology and induce toxic changes in the body that affects the individual from in utero through adulthood due to cumulative exposure [3
]. Modification of the adverse experience is key in mitigating the effects of the exposure [1
Time and place are key components of the life course framework. Time refers to not only lifetime (i.e., chronological age) but also historical time (i.e., a birth cohort). The birth cohort is the year of birth during which important environmental conditions occur that can affect the health of children in the present and could manifest at a later stage of life [1
Place is regarding a geographical location and group membership is relating to “family, friends or age, and on the basis of class, ethnicity, residence, and gender that arise out of the social and economic structure of society” [4
The changing environment one is exposed to determines and affects their risk of disease and how they respond to that risk [1
]. Accumulation of risk is a concept of the life course approach which posits that insults build up due to injury, illness, environmental conditions and health behaviors. The life course approach has the objective of testing the extent of cumulative damage to the body as the severity and duration of the exposure increases as the body grows older, it is less likely to handle the damage or repair it [4
]. Ultimately, the life course approach offers perspective on disease inclinations, and for “gender, ethnic, and geographical, inequalities in health” [4
] and is a means to understand lead exposure among U.S. adults.
Lead, a toxic metal, induces numerous adverse clinical outcomes in children and adults. Due to the widely held view that lead had the capacity to enhance engine performance by boosting octane ratings, reduce engine knocking, and optimize the performance of valve seats within motors, United States motor vehicles used gasoline containing tetraethyl lead additives from the 1920s to 1995 [5
]. It plays no role in normal human physiology and through various mechanisms, most involving taking calcium’s place in mechanisms of physiological importance, acts to induce adverse clinical outcomes [6
]. Additionally, because lead persists in the environment, populations can remain exposed in areas where it was used previously. Lead exposure has decreased significantly over the past 30 years in the U.S. because of policy-driven changes which has caused lead content to be reduced in gasoline, household paint, the food canning process, industrial emissions, and in water [8
]. However, despite the dramatic fall in lead exposure in the U.S., certain segments of the population continue to be exposed to elevated levels of lead due to their socioeconomic status, occupation, their place of residence (especially, living in disadvantaged neighborhoods), and/or their history of exposure [8
Oxidative stress, a process which produces reactive oxygen species (ROS) or reactive nitrogen species (RNS), is an imbalance between the pro-oxidants and antioxidants in the body [9
]. Pro-oxidants may be either exogenous or endogenous. The harmful effects of free ROS and RNS are potential biological damage where there is either a disproportionate production of ROS/RNS and/or a deficiency of antioxidants. The redox stress/oxidative stress is a complex process which impacts humans depending on the type of oxidant, on the composition and activities of various antioxidants on the site and intensity of action, and on the ability of repair systems [9
Under normal conditions, the physiologically important intracellular levels of reactive oxygen species (ROS) are maintained at low levels by various enzyme systems participating in the in vivo redox homeostasis.
Oxidative stress affects the vascular system, a system important to normal physiological function. With respect to vascular oxidative stress, reactive oxygen species (ROS) including such enzymatic processes as xanthine oxidase, Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and an uncoupled endothelial nitric oxide (eNOS) synthase, that possibly affects vascular tone or function, by altering it through its effects on nitric oxide (NO) signaling or bioavailability [10
]. NO that is released from endothelial cells works in concert with prostacyclin to inhibit platelet aggregation. Specifically, the NO inhibits the attachment of neutrophils to endothelial cells and the expression of adhesion molecules. In elevated concentrations, NO inhibits the multiplying of smooth muscle cells; thus whenever NO deficit is encountered, atherosclerosis may be initiated or potentially accelerated [10
]. With respect to the connection between antioxidant nutrients and lead exposure, Hsu and LeonGuo [11
] found that lead-induced oxidative stress plays a role in the pathogenesis of lead poisoning by affecting the delicate antioxidant/pro-oxidant equilibrium in cells. They found that in vivo studies suggest lead exposure induces the generation of ROS and alteration of antioxidant defense systems in occupationally exposed workers. Various markers exist for oxidative stress including erythrocytes glutathione (GSH) levels, plasma malondialdehyde (MDA), nitrite/nitrate (NOx) and homocysteine (Hcy) levels, as well as serum ceruloplasmin (Cp), total antioxidants (TAO), endothelin-1 (ET-1) levels and γ-glutamyl transferase (GGT) [12
]. In this study, GGT levels will be used as the marker of oxidative stress. Epidemiological studies have consistently suggested that serum GGT within its normal range might be an early and sensitive enzyme related to oxidative stress [13
Operationalization of Theory
The life course theoretical model will be operationalized in this study as shown in Figure 1
using variables and conditions widely reported in the literature [15
In the diagram, path A represents a biological pathway where the lead exposure is associated with adverse health outcomes in childhood and adulthood. It should be noted that lead has a half-life of up to 30 years in bone; thus, exposure in utero can continue to accumulate and induce health effects over one’s lifespan. Path B is a social pathway where one’s socioeconomic background increases their risk of exposure to lead which can subsequently accumulate over a lifetime and in the presence of new and acute exposures induce adverse health effects. Path C is the sociobiological path that indicates the social and economic status of an individual and how continuous exposure can increase over a lifetime and subsequently induces disease. Path D represents a biosocial pathway in which the consequences of extensive lead exposure results in decreased educational attainment and subsequently brings about poverty. Ultimately, what this model shows is that exposure during a key period may result in the irreversible induction of pathology [19
] which affects an individual through their lifetime. Regarding lead, when it damages some biological functions, especially in the neurological system, the damage may be irreversible making prevention vital.
Prevention starts early, during in utero as toxicity associated with lead crosses the placental barrier and the fact that it competes with calcium, thus affecting fetal and maternal bone function [20
]. Maternal bone is an endogenous source of lead; since a woman who has accumulated lead during her lifetime and in her reproductive years, may have a significant store of lead in her bones. This accumulation suggests that women who have been exposed to lead in the past are at risk of exposing the developing fetus to lead via cord blood and after birth, through breast milk [21
]. Lead exposure can then start to build up through childhood and into adulthood.
Adult Blood Lead Epidemiology Surveillance (ABLES), which monitors adult blood lead levels (BLL) in the United States [22
], adopted 5 μg/dL as the reference for elevated BLLs in adults. Lead exposure among adults mainly occurs in the workplace within lead and zinc ore mining, painting, and battery manufacturing industries. Exposure in these and other industries can occur over the course of one’s life and through mechanisms including oxidative stress and induce pathology. The current study examined lead exposure and sought to determine if it alters key life course variables in a nationally representative sample. It also sought to understand the role of oxidative stress; one of the underlying mechanisms for much of the pathology, due to lead exposure.
2. Materials and Methods
Data from NHANES 2007–2010 were used to study lead and oxidative stress biomarker GGT in the general U.S. adult population. The NHANES 2007–2010 survey, conducted by the Centers for Disease Control and Prevention (CDC), used a representative sample of the U.S. noninstitutionalized civilian population. Participants were selected using a complex sampling methodology. The sample weights for NHANES 2007–2010 were based on population estimates that incorporate the national census count. In all, 12,153 adult subjects ≥ 20 years were involved in this complex, multistage, stratified cluster survey in 2007–2010, which after considering sampling weights consisted of 217,057,187 people. Of the 12,153 participants, BLL was measured in 9781 adult subjects which represented an estimated 182,052,299 people.
NHANES 2007–2010 consisted of a standardized questionnaire and a physical examination at a Mobile Examination Center (MEC). The data is available at the organization’s homepage. Methods for data collection are on the NCHS’ website [National Center for Health Statistics, 2007–2008, 2009–2010].
2.1. Biomarkers in the Operationalized Theoretical Model
The biomarker of interest is blood lead, which is representative of current lead exposure [23
]. Blood lead level (BLL) can help determine the level of exposure but is not representative of the body burden of lead. Other biomarkers include GGT, which can be used as a measure of oxidative stress. In NHANES 2007–2010, the biochemistry biomarkers were measured via the Roche Modular P chemistry analyzer at the University of Minnesota, MN, USA and a Beckman Synchron LX20, Beckman UniCel®
DxC800 Synchron (Brea, CA, USA) at Collaborative Laboratory Services. Metal assays in whole blood samples were performed in the NHANES 2007–2010 at the Division of Laboratory Sciences, National Center for Environmental Health (NCEH) of the CDC.
2.2. Statistical Analysis
In this study, the analysis was performed on those experiencing various degrees of exposure represented by BLLs in three tertiles; 0–2 µg/dL, 2–5 µg/dL, 5–10 µg/dL, presented as tertile 1, tertile 2, and tertile 3 in this study.
The association between lead and the oxidative stress marker were examined with linear regression. Natural log transformation was used for independent and dependent variables in regression analysis as the variables of interest were not normally distributed.
Data analysis and management was done in accordance with the NHANES analytical guidelines relating to its survey design and weighting. The software Stata SE/15.0 (StataCorp, College Station, TX, USA) was used.
A p-value of <0.05 was considered significant while a value of <0.10 was considered moderately significant.