Keywords
heavy metals, inductively coupled plasma mass spectrometry, arsenic, cadmium, lead, mercury, Peru
Population-based exposure assessments for heavy metals and metalloids (by governmental and private institutions) are common in Peru, but most studies generally focus on the analysis of a single chemical element, like lead or mercury, and lack an appropriate reference regarding the health impact on the exposed population. The complex/mixed chemical interactions within the human body have not yet been studied for all long-term health effects.
We reviewed laboratory results from five studies, between 2005-2013, that analysed multiple elements (between 13 and 17 chemical elements in each study) in spot urine samples from Peruvian communities considered exposed and not exposed. All laboratory analysis were performed using inductively coupled plasma mass spectrometry (ICP-MS) at the Environmental Health Laboratory Division of the Centers for Disease Control and Prevention (CDC) of the United States.
Six chemical elements (total arsenic, caesium, cobalt, lead, molybdenum, and thallium) were present in almost all spot urine samples (>98% of participants), evidencing exposure (qualitative assessment). Exposure to other chemical elements like barium, cadmium, tungsten, antimony and uranium, varied among localities, while chemical elements like beryllium and platinum were rarely detected (<3% and <10% of participants, respectively) in spot urine samples. Most geometric means of urine concentration for total arsenic, lead, cadmium and mercury are higher for the Peruvian locations than for national estimates in Canada and the United States, but not in all locations.
Comparing averages across different populations can be misleading but comparing periodic values from the same population in the future could evidence an exposure trend. Future studies are needed to develop reference levels for exposed Peruvian populations. This study highlights potential health risks from exposure to environmental chemical elements and can be the first step towards understanding and mitigating human exposure to heavy metals and metalloids for known exposed populations in Peru.
heavy metals, inductively coupled plasma mass spectrometry, arsenic, cadmium, lead, mercury, Peru
Most human diseases rely on laboratory confirmation to establish the presence of disease, but this may be an unmet expectation in environmental exposure assessments because there is currently a knowledge gap between data generated by scientific research and the practical applications of that knowledge to Public Health interventions.1 Human exposure assessment to chemical elements is complex, and “the ability to measure chemicals in humans is far outpacing the ability to reliably interpret these data for Public Health purposes”.2 Biomonitoring (measuring chemicals in human biological samples) can fail to provide information to support Public Health decisions, mostly because results can be difficult to interpret in proper context and the absence of relevant environmental legislation produces a dangerous oversight that is common to many developing countries.3 Regardless, data from human exposure to environmental contaminants is constantly produced, creating a need to assess relationships with potential adverse health impacts and identify potential sources and pathways.2
Human exposure to environmental chemical elements by air, dust, or water, is inherent to local mining or oil extractive activities, and is a major public health issue in Peru. Environmental and biological evaluations are constantly being carried out by both governmental and private institutions to assess human exposure to different chemical elements. There are plenty of isolated reports regarding exposure to certain heavy metals/metalloids (i.e., lead and mercury) in populations considered not to be occupationally exposed (i.e., children), at levels that would be considered a clinical emergency in other countries.4–6 Suggested explanations for these apparent discrepancies in Peruvian children include genetic adaptation,7 physiological changes from living at high altitudes,8 and the interaction between chemicals inside the human body.9 These “grey literature” observational studies report high levels of heavy metals when compared to other countries, but are seldom included in the scientific literature. We summarize results from official reports of five evaluations performed in Peru by the Division of Laboratory Sciences (DLS) at the National Center for Environmental Health (NCEH) of the Centers for Disease Control and Prevention (CDC) of the United States and compare the results with national reports from other countries. The objective of the study is to identify valuable conclusions that can be drawn from CDC’s DLS analysis in Peru between 2005 and 2013.
Researchers at CDC’s DLS have been pioneers in developing laboratory techniques to measure a broad spectrum of chemical elements in human biological samples (biomonitoring),10 and their laboratories have international prestige and are considered “reference laboratories” by the World Health Organization.
All exposure assessments responded to community concerns about industrial contamination of natural resources (Figure 1). The city of La Oroya (3745 meters above sea level) includes one of the largest smelting facilities in the world. Three communities are within the area of influence of open pit mines: the province of Espinar (3929 m.a.s.l.), the town of Ayash (3503 m.a.s.l.) is downstream from a top-five world copper production mine, and the Andean capital of Cerro de Pasco (4330 m.a.s.l.) was built over an ancient Pre-Columbian silver mine. Huepethue (414 m.a.s.l.) is a modern day “boom town” in the rainforest where prospectors from all over the world arrive looking for gold in the Amazon riverbeds.
All studies focused on a subgroup of the total population. Three assessments (Ayash, Huepethue, and Espinar) relied on convenience sampling to recruit participants, and two studies in La Oroya and Cerro de Pasco included random sampling.
At the request of Peruvian health authorities, five multi-element evaluations in five populations in Peru (Table 1) were conducted at CDC’s DLS to determine the “spot” (collected at a single time point) urine concentrations of up to 17 chemical elements by laboratory analytical methods using inductively coupled plasma with mass spectrometry (ICP-MS). The elements analysed include alkali metals (caesium), alkaline earth metals (barium, beryllium, strontium, uranium), metalloids or semi-metals (antimony, arsenic), transition elements (cadmium, cobalt, manganese, mercury, molybdenum, platinum, tungsten), and base metals (tin, lead, thallium). All the studies were approved by Ethics Committees both in Peru and in the United States, and all culminated in reports for the Regional Health Directorates (DIRESAS for its acronym in Spanish), which are local branches of the Peruvian Ministry of Health (MoH). Most of these assessments include a questionnaire, but here we will only detail tabulated laboratory results.
La Oroya11 | Ayash12 | Cerro de Pasco13 | Huepethue14 | Espinar15 | |
---|---|---|---|---|---|
Department (“State”) | Junín | Ancash | Pasco | Madre de Dios | Cusco |
Case Sampling Location | La Oroya | Santa Cruz de Pichiú | Chaupimarca, Ayapoto & Paragsha | Huepethue | Alto Huancané & Huisa |
“Control” Location | Concepción | 5 other | none | none | none |
Technical Assistance Request to CDC from: | Huancayo Archbishop | MoH thru PAHO | MoH thru PAHO | MoH | Peruvian NIH |
Ethics Review Board in Peru that approves study: | Peruvian NIH | “Cayetano Heredia” University | “Dos de Mayo” Hospital | MoH | Peruvian NIH |
Date of Protocol approval: | Jun 20, 2005 | April 2007 | Jan 7, 2013 | ||
Field Team | University of Saint Louis, Missouri | CDC | CDC | CDC y Peruvian NIH | Peruvian NIH |
Local counterparts | DIRESA | DIRESA | DIRESA | DIRESA | DIRESA |
Collection Date | August 2005 | April 4-14, 2006 | May 21-Julio 4, 2007 | July 2010 | January 16-18, 2013 |
Sampling | random | convenient | random | convenient | convenient |
Selection of Participants | general population | > 5 years of age | children and women at childbearing age | general population | general population |
Number of Participants | 343 | 253 | 354 | 98 | 180 |
Range of Ages (in years) | 0.5-80 | 5-85 | 1-12 & 15-45 | 4-70 | 4-83 |
Male Percentage | 59% | 52% & 100% | 54% | 48% | |
Chemical Elements | 14 | 13 | 13 | 17 | 17 |
Date of Final Report | December 2005 | February 21, 2007 | May 1, 2008 | August 28, 2013 | |
Other samples | blood & environmental | blood | blood & environmental | blood | environmental |
The percentage of urine samples with a detectable concentration for each chemical element is presented in Figure 2 and geometric means for four elements are plotted in Figure 3. The National Health and Nutrition Examination Survey (NHANES) in the United States is designed to assess the health and nutritional well-being of children and adults using a representative sample (noninstitutionalized, civilian) of the entire population.16 Findings from the NHANES survey are used to determine the prevalence and risk factors of major diseases and are also the basis for national standards.17 Data from national surveys help develop public health policy, health programs and services, and expand the scientific knowledge on a population’s health,18,19 but biomarker measures from NHANES are not useful for demonstrating temporality, nor are they useful for evaluating causation or reverse causation.20
Note: Strontium, manganese, mercury, and tin were only reported in 2 of the exposure assessments.
There are some very specific considerations needed before appropriately interpreting these results from spot urine samples regarding the presence or absence of exposure: 1) representativeness, 2) limit of detection, 3) chronic exposure, 4) the variability of spot blood or urine levels, and 5) no universal “safe” level.
Bias is inherent to convenient sampling. Also, minimum sample size was not achieved, so the results from any of these assessments cannot be extrapolated outside the study participants.
ICP-MS has a level of detection (LOD) below which it cannot determine the presence of a particular chemical element. The LOD has decreased significantly over the years, while the number of chemical elements analysed has increased (Table 1).
Exposures to high doses in a short period of time (acute) to chemical elements are well documented, mostly in occupational or accidental settings. In most acute cases, there is usually no previous exposure levels, and blood monitoring shows a “peak” in the levels of the chemical element that progressively declines as the body eliminates the toxic threat in the urine (sometimes with concomitant treatment with chelating agents), and life-threatening blood levels have been well correlated with clinical symptoms, so constant blood monitoring in a hospital setting (or using a 24-hour urine with creatinine correction) is suggested. In a different way, cases of low doses over a long period of time (chronic) exposures may not be aware of signs and symptoms of disease and may not even be aware they have been exposed, making it difficult to identify when the exposure began. The incubation or latency period can take years and the cause for disease is generally multifactorial. Consequently, unaware patients are more likely not to seek medical attention, allowing the toxic effect to go unconstrained so a spot blood or urine sample will not differentiate between past or current exposure.
Urine is the product of blood filtration, so the decision between spot blood or urine sample is usually more of a “practical” concern (invasive vs. non-invasive procedure), considering potential cases have no apparent disease and cannot yet be considered a patient. Still, spot measurements of chemical biomarkers may not be a reliable surrogate for average or peak exposure levels.21 Blood or urine levels vary constantly during the day because the chemical element present at any time in body fluids represents not only that which has been recently ingested, breathed, or eaten, but also that which has been metabolized previously in the body tissue “reserves” (for example, bones and fat), with individual variations between metabolic rates, urinary flow or creatinine excretion rates.21 In this way, environmental chemicals acquire a role in the body’s physiological processes, entering and leaving the tissues, changing their concentration in blood and eventually, urine. Measurement errors associated with spot measures reflect variable exposures and rapid biological clearance that contribute to exposure misclassification and increase the likelihood for biased statistical associations.22
For some metals like lead and mercury, reference levels exist based on empirical biomarker–response relationships from epidemiological studies, but for most other chemical elements reference levels are not available.23 When any level of a certain metal/metalloid in body fluids is considered potentially dangerous in the long term (i.e., lead poisoning), primary prevention (avoiding exposure altogether) can be the only viable public health alternative.24 This attitude is relatively new. Until relatively recently, blood lead levels were believed to have a correlation with the clinical manifestations presented by chronically exposed people (especially children). The lead poisoning pandemic progressively showed that exposures to very low doses of lead in the environment over long periods of time can be toxic, even without clinical symptoms.2 The existence of a “safe level” (a concentration below which the risk is considered negligible) was initially desired and assumed, but studies continued to show harmful subclinical effects in young children brain development, each time at lower blood lead level.25,26 Thus, the CDC’s “level of concern” for blood lead in children progressively decreased from 40 μg/dL in the 1970s to 10 μg/dL in the 1990s (later adopted by the WHO). These “levels of concern” for blood lead were not based on any correlation with clinical symptoms, but rather with the 95th percentile in a sample population of the United States, were designed to trigger Public Health interventions and were never intended to guide individual treatment or prognosis. Instead of adopting the next “level of concern” at 5 μg/dL, in 2012 the CDC concluded that “there is no safe level for blood lead free of risk to the health of children”.27
Five environmental exposure assessments analysed spot urine samples from the following study populations: 343 participants from La Oroya in 2005;11 253 participants from Ayash in 2006;12 354 participants from Cerro de Pasco in 2007;13 98 participants from Huepethue in 2010;14 and 180 participants from Espinar in 201315 (Figure 1 & Table 1).
Evidence of exposure – Qualitative analysis For this analysis, any “detectable” level (above the LOD) is considered evidence of “exposure”, regardless of the amount detected. The percentage of spot urine samples with evidence of exposure varied between locations (Figure 2, data not available for La Oroya). Six chemical elements (total arsenic, caesium, cobalt, molybdenum, lead and thallium) were detected in almost all samples tested (average over 98%), while two other elements (beryllium and platinum) were very seldom detected, <3% and <10% respectively. Other chemical elements like barium, cadmium and tungsten were reported (on average) to be present in over 90% of all samples, while antimony (range 51-96%) and uranium (range 41-83%) were variably prevalent in different locations. Exposure to antimony was more frequent (96%) in samples from participants in Cerro de Pasco, and less frequent (<65%) in other locations. Similarly, uranium was detected more frequently (between 68% and 83%) in 3 Andean locations (Ayash, Cerro de Pasco, and Espinar), but less frequently (41%) in urine samples from the rainforest town at Huepethue. Data for strontium, mercury, manganese, and tin was available for 2 of the 5 locations (Figure 2).
Comparison among populations – Quantitative analysis For this analysis, urine concentration geometric means were retrieved from official reports for selected chemical elements and compared to geometric means from nationally representative studies in the United States28 and Canada,29 that are also available in France.30 The (not statistically valid) comparison was made for 3 of the 5 sites using geometric means and estimated 95th percentile in the United States. Chemical elements like total arsenic and lead appear to have a higher geometric mean in Peru when compared to national averages from the United States and Canada, but cadmium and mercury have a lower geometric mean in some locations in Peru (Figure 3).
The health implications for environmental exposure vary among chemical elements and the sources of environmental contaminants vary by location. In Peru, total arsenic, caesium, cobalt, lead, molybdenum, and thallium are almost universally present in urine samples from all five locations. However, there are some key issues that must be considered before attempting to assess human impact from exposure to chemical elements: 1) these are complex/mixed exposures, 2) there is individual variability, and 3) the potential confounding factor from natural exposure.
Complex exposures People can be exposed to more than one chemical at the same time, and studies analysing only one chemical element at a time ignore the potential interactions between chemicals inside the human body. These interactions can range from synergy (a cooperation of two or more substances to produce a combined effect greater than the sum of their separate effects) to antagonism (a substance acts against or blocks the action of another substance). Much remains unknown about the health effects of these mixed interactions where several environmental toxics (including heavy metals, pesticides, and hydrocarbons), from different environmental sources (natural and/or artificial), and through different environmental exposure pathways (air, soil, water and food) can increase the risk of developing diseases. Few human exposure studies analyse multiple elements from a single biological sample, and even when they do, reference information regarding health effects may not be available for all detectable elements.
Disease can be expressed in a different way and at a different time by different people, which complicates the interpretation of spot biomonitoring for Public Health action. Every person’s age, nutritional, socioeconomic and developmental status affects the human body’s ability to absorb, metabolize and excrete the toxic agent, and when and how these exposures manifest clinically. Children, for example, are considered at higher risk due to their increased metabolism and may be currently exposed to hundreds of known chemicals that have not been tested for their toxicity and their effect on human development.31,32
When trying to identify health effects for an exposed population, it is common practice to compare exposure levels to similar non-exposed populations (i.e., case-control studies), but finding an appropriate comparison group can be complicated, especially when the extension of the exposure has not been well defined and the control group (considered to be not exposed) actually has some exposure level that the researchers were not aware of.33 For example, arsenic is a known contaminant of natural water sources in Latin America, regardless of the presence or absence of industry.34 These “exposures of unknown origin” are not exclusive to developing countries, and some heavy metals are detected regularly in not-occupationally exposed populations in the Unites States (although sometimes in minimal concentrations) including blood and urine of children31 and pregnant women.35,36
Some Peruvians are exposed to several chemicals. Biomonitoring alone does not explain at what time, dose, and for how long the exposure occurred, which is essential to estimate the health impact of the inadvertent exposure. Relevant reference levels should be developed for each exposed population. Meanwhile, biomonitoring studies can help prioritize Public Health strategies for different populations in Peru.
The data for this article consists of bibliographic references, which are included in the References section.
We would like to thank Ellen E. Yard, Laura Conklin, Fuyuen Y. Yip, the lead investigators of the studies, for their support on making available data required for this study. A la Dirección de Investigación de la Universidad Peruana de Ciencias Aplicadas por el apoyo bridado para realización de este trabajo de investigación a través del incentivo UPC-EXPOST-2024-1.
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Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Partly
Are sufficient details of methods and analysis provided to allow replication by others?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: environmental behavior and risk assessment of heavy metals
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Partly
References
1. Nunzio AD, Giarra A, Toscanesi M, Amoresano A, et al.: Comparison between Macro and Trace Element Concentrations in Human Semen and Blood Serum in Highly Polluted Areas in Italy.Int J Environ Res Public Health. 2022; 19 (18). PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed.
Reviewer Expertise: effects of heavy metals and others pollutants on the reproductive health of human and marina orgsnisms
Alongside their report, reviewers assign a status to the article:
Invited Reviewers | ||
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