Determining “safe” levels of exposure: The validity of the use of 10X safety factors

The current guideline for risk assessment of chemicals having a toxic end point routinely uses the reference dose (RfD) approach based on uncertainty factors of 10. With this method the quality of individual risk assessment varies among chemicals, often resulting in either an over‐ or under‐estimation of adverse health risk. The purpose of this investigation is to evaluate whether the magnitude of the 10X uncertainty factors have scientific merit against data from published experimental studies. A compilation and comparison of ratios between LOAEL/NOAEL (Lowest Observed Adverse Effect Level/No Observed Adverse Effect Level), subchronic/chronic, and animal/human values were made. The results of the present investigation revealed that the use of default factors could be over‐conservative or unprotective. More reasonable estimates of the risk to human health would result in a reduction of unnecessary, and expensive over‐regulation. In addition to the LOAEL to NOAEL, and subchronic to chronic ratios, the adequacy of uncertainty factors for animal to human extrapolations were examined. Although a 10‐fold uncertainty factor (UF) is most commonly used in the risk assessment process, an examination of the literature for the compounds presented here suggests that the use of different values is scientifically justifiable.     

Noncancer Risk Assessment: A Probabilistic Alternative to Current Practice

Based on imperfect data and theory, agencies such as the United States Environmental Protection Agency (USEPA) currently derive “reference doses” (RfDs) to guide risk managers charged with ensuring that human exposures to chemicals are below population thresholds. The RfD for a chemical is typically reported as a single number, even though it is widely acknowledged that there are significant uncertainties inherent in the derivation of this number.

In this article, the authors propose a probabilistic alternative to the EPA's method that expresses the human population threshold as a probability distribution of values (rather than a single RfD value), taking into account the major sources of scientific uncertainty in such estimates. The approach is illustrated using much of the same data that USEPA uses to justify their current RfD procedure.

Like the EPA's approach, our approach recognizes the four key extrapolations that are necessary to define the human population threshold based on animal data: animal to human, human heterogeneity, LOAEL to NOAEL, and subchronic to chronic. Rather than using available data to define point estimates of “uncertainty factors” for these extrapolations, the proposed approach uses available data to define a probability distribution of adjustment factors. These initial characterizations of uncertainty can then be refined when more robust or specific data become available for a particular chemical or class of chemicals.

Quantitative characterization of uncertainty in noncancer risk assessment will be useful to risk managers who face complex trade-offs between control costs and protection of public health. The new approach can help decision-makers understand how much extra control cost must be expended to achieve a specified increase in confidence that the human population threshold is not being exceeded.     

Initial Risk-Based Screening of Potential Brownfield Development Sites

Brownfield redevelopment is sustainable only when it is a transparent process protective of public health. The objective of the brownfield health risk screening matrix is to provide a scientifically based, transparent process to evaluate human health risks on proposed redevelopment sites as well as a framework that can be critically evaluated by both environmentalists and the community in general. Public discussion and understanding of current health risk assessment, as well as the risks specific to each brownfield redevelopment site, are essential for an effective brownfield redevelopment program.

The Brownfields Redevelopment Program was started by the EPA in 1995 and seeks to use already contaminated sites rather than contaminate even more greenfields. Two of the biggest difficulties are making redevelopment profitable and protecting human health. Traditional human health risk assessment evaluates single chemical exposures and identifies the level below which no adverse effect will occur to the most sensitive subgroups of the population. For cancer–causing chemicals the risk must be lower than 1:1,000,000. When brownfield redevelopment sites are associated with high cost, extensive time and unmanageable uncertainty, additional greenfield sites will become contaminated and the contamination on current brownfield sites will remain un-remediated.

The citizens' advisory group addressing brownfields in a southern New York county has developed a risk matrix to evaluate the uncertainty of the available data, the toxicity of the known or suspected contaminants and the likely exposure routes for each brownfield site in the county. The matrix categorizes sites as high, medium or low risk according to exposure groups. The risk matrix complements the triad approach currently being developed by EPA to identify and manage project decision uncertainties, addresses uncertainty as well as toxicity and has the potential to reduce the cost of traditional health risk assessment at brownfield redevelopment sites.     

Association of IL-10 (-819T/C, -592A/C and -1082A/G) and IL-6 -174G/C gene polymorphism and the risk of pneumonia-induced sepsis

Context: Association between inherited variants and the risks of sepsis is controversial.

Objective: To evaluate the risk of pneumonia-induced sepsis by examining its linkage with polymorphisms of IL-6 and IL-10.

Materials and methods: Samples were obtained from 188 pneumonia-induced sepsis patients, 162 pneumonia patients and 200 healthy controls.

Results: Subjects with IL-10 -1082 AA genotypes and IL-6 -174?CC genotype had a higher risk of sepsis and increased mRNA levels.

Conclusion: The variants of IL-10 -1082 A allele and IL-6 -174 C allele contributed to an increased risk of pneumonia-induced sepsis.     

The relationship of single-strand breaks in DNA to breast cancer risk and to tissue concentrations of oestrogens

Context: Clinical study of breast cancer patients in Chicago, IL, USA.

Objective: Ascertain the utility of measurements of single-strand breaks (SSB) in DNA for assessment of breast cancer risk.

Methods: Fine-needle aspirates of the breast, SSB by nick translation, percent breast density (PBD), Gail model risk, cumulative methylation index (CMI), enzymes of DNA repair and tissue antioxidants.

Results: DNA repair enzymes and 4-hydroxyestradiol were negatively associated with SSB; CMI and PBD were positively associated.

Conclusions: Quantitative measurement of SSBs by this procedure indicates the relative number of SSBs and is related to promoter methylation, antioxidant availability and percent breast density.     

In Defense of Risk Assessment: A Reply to the Environmental Justice Movement's Critique

The environmental justice movement believes risk assessment is undemocratic. The movement believes risk assessment is a way of trading human health for profit and a means of legitimizing exposure to toxic chemicals. The movement considers risk assessment an evil industry and a tool developed by those who wish to oppress racial and ethnic minorities. These beliefs are wrong and the environmental justice movement is a Luddite enterprise. Risk assessment is a fundamentally democratic process and enables all people, regardless of race, ethnicity, income or social status, to enjoy the benefits of technology and also suffer its drawbacks within a framework of equality and democracy. “A savage servility slides by on grease.” -Robert Penn Warren For the Union Dead

     

Circulating microparticles in cardiovascular disease: going on stage!

Context: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. In spite of the fact that treatments are based on risk calculators which in turn are based on population characteristics, it is well known that these methods have definite levels of uncertainty. Recently, more precise diagnostic or predictive methods have been developed based on indicators of vascular and/or cardiac damage in order to supplement this risk evaluation.

Objective: In this review, we describe the main discoveries leading to the idea of using circulating microparticles as a promising and complementary tool in the evaluation of cardiovascular risk.

Methods: A Medline search for the terms cardiovascular diseases, microparticles, miRNAs, diagnosis, prognosis, biomarkers and microvesicles was performed.

Results: We found (i) nine articles, which were relevant to forming the idea of using microparticles as biomarkers in CVDs, and (ii) 15 and 12 experimental clinical studies which describe their potential in primary and secondary CVD prevention, respectively.

Conclusions: The levels of circulating microparticles have been associated with cardiovascular damage in asymptomatic patients as well as in patients who suffered a cardiovascular event, becoming promising diagnostics or prediction biomarkers in recent years.     

Propeptide big-endothelin,N-terminal-pro brain natriuretic peptide and mortality. The Ludwigshafen risk and cardiovascular health (LURIC) study

Context: The endothelin system (Big-ET-1) is a key regulator in cardiovascular (CV) disease and congestive heart failure (CHF).

Objectives: We have examined the incremental value of Big-ET-1 in predicting total and CV mortality next to the well-established CV risk marker N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP).

Methods: Big-ET-1 and NT-proBNP were determined in 2829 participants referred for coronary angiography (follow-up 9.9 years).

Results: Big-ET-1 is an independent predictor of total, CV mortality and death due to CHF.

Discussion: The conjunct use of Big-ET-1 and NT-proBNP improves the risk stratification of patients with intermediate to high risk of CV death and CHF.

Conclusions: Big-ET-1improves risk stratification in patients referred for coronary angiography.     

A Regional Retrospective Assessment of the Potential Stressors Causing the Decline of the Cherry Point Pacific Herring Run

The Pacific herring stock that spawns at Cherry Point, northwest of Bellingham, WA, has undergone a dramatic decline in the last 20 years. The population decline corresponds with a collapse of the age structure. The Cherry Point area contains three deep water shipping piers, two refineries, an aluminum smelter, and urban development. The Cherry Point Aquatic Reserve was formed initially to protect the spawning habitat of the Cherry Point Pacific herring run. We conducted a retrospective assessment using the relative risk model (RRM) to investigate the causes of the current decline of the Cherry Point run. The RRM combines aspects of the weight-of-evidence (WoE) approach and other methods of establishing causality into a framework that deals with multiple stressors, uncertainty, and spatial scale.

An analysis of the Cherry Point Pacific herring age structure and population dynamics indicates that the loss of reproductive potential of the older age class fish was the population characteristic that led to the decline of the run. Exploitation, habitat alteration and climate change are the risk factors that contribute to the decline of the Cherry Point Pacific herring. The retrospective assessment identified the cyclic nature of climate change, as expressed by the warmer sea surface temperatures associated with a warm Pacific Decadal Oscillation (PDO), as the primary factor altering the dynamics of the Pacific herring. Other factors are ranked accordingly along with the associated uncertainty. Criteria for selecting alternative endpoints for managing the Cherry Point Aquatic Reserve are also provided.

The strengths of the retrospective RRM include its ability to combine a WoE and causality criteria with a multitude of stressors at a regional scale. The difficulties include how to deal with differences in the magnitude of effects, and expressing the uncertainty as distributions.     

Association between high-sensitivity cardiac troponin T and future cardiovascular incidence in a general Japanese population: results from the Tohoku medical megabank project

Purpose: Elevation of high-sensitivity cardiac troponin T (hs-cTnT) is associated with an increased risk of cardiovascular disease (CVD). This study determined whether hs-cTnT was detectable with N-terminal pro-b-type natriuretic peptide (NT-proBNP) and related to CV risk factors in a general Japanese population.

Materials and methods: The Tohoku Medical Megabank Organization pooled individual participant data for a population-based cohort study in the Iwate prefecture (n?=?30,193, age = 60.2?±?11.5?year).

Results: Hs-cTnT levels were higher in participants with hypertension, diabetes mellitus than in participants without these conditions (all ps < 0.001). Logistic regression analysis demonstrated that NT-proBNP was strongly associated with elevation of hs-cTnT (OR = 3.35, 95% CI = 2.90–3.89, p?<?0.001). The receiver operating characteristic curve analysis showed that hs-cTnT was one of useful biomarker for the differentiation of high risk for CVD (the Suita score ≥ 56) from a general population. Logistic regression analysis demonstrated hs-cTnT levels were related to the CVD high risk group (OR = 2.67, 95% CI = 2.28–3.14, p?<?0.001).

Conclusions: Hs-cTnT levels are associated with elevation of NT-proBNP and high Suita score, which suggests that elevated hs-cTnT is related to subclinical myocardial damage and indicates CV risk.     

Matrix metalloproteinase multiplex screening identifies increased MMP-2 urine concentrations in women predicted to develop preeclampsia

Background: Preeclampsia, a pregnancy disorder characterized by hypertension and proteinuria, represents the leading cause of fetal and maternal morbidity and mortality in developing countries. The identification of novel and accurate biomarkers that are predictive of preeclampsia is necessary to improve the prognosis of patients with preeclampsia.

Objective: The objective of this study is to evaluate the usefulness of nine urinary metalloproteinases to predict the risk of preeclampsia development.

Methods: MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12 and MMP-13 were analyzed in urine (early-pregnancy) from 17 women predicted to develop preeclampsia and 48 controls using the Bio-Plex Pro-Human MMP panel (Bio-Rad, Hercules, CA).

Results: Urinary MMP-2 showed differences between groups which allowed us to calculate an increased risk for PE development of up to 20 times among the study population.

Conclusion: Increased urinary concentration of MMP-2 at 12 and 16 weeks of gestation predicted an increased risk of developing preeclampsia in the study population.     

Quantification of 1-hydroxypyrene, 1- and 2-hydroxynaphthalene, 3-hydroxybenzo[a]pyrene and 6-hydroxynitropyrene by HPLC-MS/MS in human urine as exposure biomarkers for environmental and occupational surveys

Context: Several urinary PAHs metabolites can be detected by HPLC-MS/MS for individual exposure assessment.

Objective: Quantitation of urinary metabolites of four PAHs, selected on the basis of their significance, with reduced costs and high sensitivity.

Materials and methods: HPLC-MS/MS was used and pure standards and isotope-labeled internal analogs of the analytes. Two hundred samples were tested after enzymatic hydrolysis.

Results: Accuracy was higher than 90% and variability lower than 19%; LODs permit to measure 1-hydroxypyrene, 1 and 2-hydroxynaphthalene in all subjects, 6-hydroxynitropyrene in the 65% and 3-hydroxybenzo[a]pyrene in the 70%.

Discussion and conclusion: The method is suitable both for occupational and for environmental studies. This is the first paper reporting urinary levels of 6-hydroxynitropyrene in European subjects, nonoccupationally exposed to nitro-PAHs.     

Circulating adiponectin as a biomarker in renal cell carcinoma: a systematic review and meta-analysis

Context: Metabolic imbalance in renal cell carcinoma (RCC) can lead to abnormal adiponectin levels.

Objective: To evaluate circulating adiponectin as a detection or predictive marker for RCC.

Methods: A comprehensive literature search and meta-analysis was performed on studies reporting circulating adiponectin levels and RCC. The meta-analysis was performed using RevMan.

Results: Seven studies compared the circulating adiponection levels between RCC cases and controls. Adiponectin level was significantly lower in RCC cases compared to controls at pre-diagnosis and pre-operative time-points. RCC stage, grade and subtype did not affect adiponectin levels.

Conclusion: Low circulating adiponectin could be a predictive or risk factor for RCC.     

Differential expression of circulating vascular cell adhesion molecule-1 in subjects with coronary artery disease and cardiac syndrome X without known diabetes mellitus

Context: Inflammation is one of the mechanisms underlying cardiac syndrome X (CSX).

Objectives: Few studies have compared the expression of inflammatory or adhesion molecules between coronary artery disease (CAD) versus CSX.

Materials and methods: Ninety-two CSX and 145 CAD subjects without known diabetes mellitus underwent coronary angiogram for angina.

Results: Vascular cell adhesion molecule (VCAM)-1 (median, 507 versus 431?ng/ml, p?=?0.001) was significantly higher in the CAD group. In the binary regression, VCAM-1 was a significant differential factor for CAD versus CSX.

Discussion and conclusion: Adhesion molecules might be implicated in the differential expression of macro versus microvascular coronary disease.

Trial registration number: NCT01198730 at https://clinicaltrials.gov     

Pre-fledging survival in a Yellow-legged Gull Larus michahellis population in northern Iberia is mostly determined by hatching date

Capsule: Pre-fledging survival in a Yellow-legged Gull Larus michahellis population in northern Iberia is negatively correlated to hatching date.

Aims: To explore which factors have more importance in determining the pre-fledging daily survival rates in a Yellow-legged Gull population from northern Iberia. Specifically, we tested for the effect of hatching date and order, body size and condition and meteorological conditions on pre-fledging survival.

Methods: Cormack–Jolly–Seber models with mixtures were used to model daily survival rates.

Results: Daily survival rates were mostly negatively affected by hatching date.

Conclusions: Hatching date was the most important factor affecting survival of chicks during the pre-fledging period in a Yellow-legged Gull colony from northern Iberia.     

Urinary D-serine level as a predictive biomarker for deterioration of renal function in patients with atherosclerotic risk factors

Background: D-serine, the enantiomer of L-serine, was identified in mammals 20?years ago. Although a close relationship between D-serine and renal dysfunction has been shown, the clinical implications of urinary D- and L-serine in humans are poorly understood. The aim of this study was to evaluate the relationship between urinary D- and L-serine with well-known renal biomarkers, and clarify the prognostic value of D- and L-serine for renal events.

Methods: This cross-sectional, prospective study included 65 patients with atherosclerotic risk factors, who were followed up for a median of 16?months. The primary endpoint was a composite of end-stage renal disease and a decline in estimated glomerular filtration rate (eGFR)?≥?25% from baseline.

Results: Urinary D-serine concentrations showed a better correlation with eGFR than did urinary L-serine, whereas neither urinary D- nor L-serine correlated with tubular markers such as urinary liver-type fatty acid-binding protein and N-acetyl-beta-D-glucosaminidase. A Cox regression analysis revealed that low urinary D-serine levels were significantly associated with the primary endpoint after adjusting for confounding factors (hazard ratio 12.60; 95% confidence interval, 3.49–45.51).

Conclusions: Urinary D-serine is associated with glomerular filtration and can be a prognostic biomarker of renal dysfunction in patients with atherosclerotic risk factors.     

Biomarker discovery for drug-induced phospholipidosis: phenylacetylglycine to hippuric acid ratio in urine and plasma as potential markers

Context: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable.

Objective: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach.

Method: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs.

Results: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation.

Conclusion: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.     

A Deterministic Method for Deriving Site-Specific Human Health Assessment Criteria for Contaminants in Soil

A method for deriving Site-Specific Assessment Criteria (SSAC) for use when considering risk to human health from chronic exposure to heavy metals (except lead), metalloids, and organic substances in soil, with application to the United Kingdom (UK), is described. The SSAC represents the soil concentration above which an unacceptable risk to human health may be indicated.

The method considers the UK standard land uses (residential with and without plant uptake, allotment gardens, and commercial/industrial) by applying the default exposure factors and algorithms provided. Non-standard land uses can be also considered. Site-specific determinations of contaminant bioaccessibility or of plant-to-soil concentration factors may be used if available.

The method adopts the risk-based source-pathway-receptor pollutant linkage framework and a deterministic methodology. Exposure pathways considered are direct ingestion of soil and dust, consumption of home grown or allotment vegetables, ingestion of soil attached to such vegetables, inhalation of soil vapors outdoors and inhalation of soil vapors indoors. A test for the significance of the dermal pathway is also included.

It is not intended that the method be used to generate or replace UK Soil Guideline Values, because this can only be done by the appropriate authoritative bodies within the UK (Department of the Environment, Food and Rural Affairs and the Environment Agency).     

Future breeding and foraging sites of a southern edge population of the locally endangered Black Guillemot Cepphus grylle

Capsule: One of the southernmost populations of the Black Guillemot Cepphus grylle is currently endangered, and the risk may be exacerbated by climate change.

Aims: We evaluated the future vulnerability of the Black Guillemot by predicting the impact of climate change on the geographic distribution of its breeding and foraging range in the Baltic Sea.

Methods: We used MaxEnt, a species distribution modelling technique, to predict the current and future breeding grounds and foraging sites.

Results: We found that although the foraging range is expected to increase in the southern Baltic Sea in future, these areas will no longer be suitable as breeding grounds due to a changing climate, creating a spatial mismatch.

Conclusion: Our predictions indicate where threats to the species may be most severe and can be used to guide conservation planning. We advocate conservation measures which integrate potential future threats and focus on breeding sites across the current and future potential geographic range of the Black Guillemot.     

Lipoprotein-associated phospholipase A2, and subsequent cardiovascular events and mortality among patients with coronary heart disease

Objective: The objective of this study is to evaluate the relevance of Lp-PLA₂ to risk prediction among coronary heart disease (CHD) patients.

Methods: Lp-PLA₂ activity was measured in 2538 CHD patients included in the Bezafibrate Infarction Prevention (BIP) study.

Results: Adjusting for patient characteristics and traditional risk factors, 1 standard deviation of Lp-PLA₂ was associated with a hazard ratio (HR) of 1.12 (95% confidence interval (CI): 1.00–1.25) for mortality and 1.03 (0.93–1.14) for cardiovascular events. Lp-PLA₂ did not significantly improve model discrimination, or calibration nor result in noteworthy reclassification.

Conclusions: Our results do not support added value of Lp-PLA₂ for predicting cardiovascular events or mortality among CHD patients beyond traditional risk factor.