Lost in the woods: Finding our way back to the scientific method in systematic review.

Systematic review has become the preferred approach to addressing causality and informing regulatory and other decision-making processes, including chemical risk assessments. While advocates of systematic reviews acknowledge that they hold great potential for increasing objectivity and transparency in assessments of chemicals and human health risks, standardizing and harmonizing systematic review methods have been challenging. This review provides a brief summary of the development of systematic review methods and some of the frameworks currently in use in the US and Europe.

Resolving an Open Science-policy question: Should the LNT still be an omnibus regulatory assumption?

Regulatory analyses, modeling the carcinogenic effect of ionizing radiations (IR) (e.g., alpha and beta particles, x-, and gamma rays, neutrons) and chemicals continue to use the linear no-threshold (LNT) model from zero to some low dose.

Ionizing radiations epidemiology does not support the LNT model.

Most cancers are multifactorial diseases. Yet, epidemiological modeling of the effect of ionizing radiation (IR) exposures based on the linear no-threshold model at low doses (LNT) has generally not included co-exposure to chemicals, dietary, socio-economic and other risk factors also known to cause the cancers imputed to IR. When so, increased cancer incidences are incorrectly predicted by being solely associated with IR exposures.

Quantifying the risk-reduction potential of new Modified Risk Tobacco Products.

Quantitative risk assessment of novel Modified Risk Tobacco Products (MRTP) must rest on indirect measurements that are indicative of disease development prior to epidemiological data becoming available. For this purpose, a Population Health Impact Model (PHIM) has been developed to estimate the reduction in the number of deaths from smoking-related diseases following the introduction of an MRTP. One key parameter of the model, the F-factor, describes the effective dose upon switching from cigarette smoking to using an MRTP.

Assessing Catastrophes-Dragon-Kings, Black, and Gray Swans-for Science-Policy.

The threat of catastrophic incidents-from nonroutine events to extreme ones, such as Dragon-Kings (DK), Black Swans (BS), and Gray Swans-induces precautionary initiatives that, before the fact, may encounter public resistance or after the fact recriminations. This study develops three aspects of these events: (1) generating mechanisms, (2) the statistical distributions of near and far-term consequences, and (3) the aggregation of expert opinions about assumptions, mechanisms, and consequences that informs science-policy. This study shows how causal analysis should account for the: (1) nonlinear catastrophic behaviors that generate predictions, (2) common and power-law distributions of the consequences, (3) self-organizing criticality and self-similarity, and (4) feedbacks and couplings between mechanisms that produce snaps, crackles, and pops as precursor, warning signals.

Endocrine Disruptors: Improving Regulatory Science Policy.

Law and science combine in the estimation of risks from endocrine disruptors (EDs) and actions for their regulation. For both, dose-response models are the causal link between exposure and probability (or percentage change) of adverse response. The evidence that leads to either regulations or judicial decrees is affected by uncertainty and limited knowledge, raising difficult policy issues that we enumerate and discuss.

Warmer is healthier: effects on mortality rates of changes in average fine particulate matter (PM2.5) concentrations and temperatures in 100 U.S. cities.

Recent studies have indicated that reducing particulate pollution would substantially reduce average daily mortality rates, prolonging lives, especially among the elderly (age ≥ 75). These benefits are projected by statistical models of significant positive associations between levels of fine particulate matter (PM2.5) levels and daily mortality rates.

Regulatory-Science: Biphasic Cancer Models or the LNT-Not Just a Matter of Biology!

There is no doubt that prudence and risk aversion must guide public decisions when the associated adverse outcomes are either serious or irreversible. With any carcinogen, the levels of risk and needed protection before and after an event occurs, are determined by dose-response models. Regulatory law should not crowd out the actual beneficial effects from low dose exposures-when demonstrable-that are inevitably lost when it adopts the linear non-threshold (LNT) as its causal model.

Temperature, Not Fine Particulate Matter (PM2.5), is Causally Associated with Short-Term Acute Daily Mortality Rates: Results from One Hundred United States Cities.

Exposures to fine particulate matter (PM2.5) in air (C) have been suspected of contributing causally to increased acute (e.g.

Systems Cancer Biology and the Controlling Mechanisms for the J-Shaped Cancer Dose Response: Towards Relaxing the LNT Hypothesis.

The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transformation frequency.

Water quality and non-point sources of risk: the Jiulong River Watershed, P. R. of China.

Retrospective water quality assessment plays an essential role in identifying trends and causal associations between exposures and risks, thus it can be a guide for water resources management. We have developed empirical relationships between several time-varying social and economic factors of economic development, water quality variables such as nitrate-nitrogen, COD(Mn), BOD(5), and DO, in the Jiulong River Watershed and its main tributary, the West River. Our analyses used alternative statistical methods to reduce the dimensionality of the analysis first and then strengthen the study's causal associations.

Modeling Dose-response at Low Dose: A Systems Biology Approach for Ionization Radiation.

For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses.

Causal regulations vs. political will: why human zoonotic infections increase despite precautionary bans on animal antibiotics.

Using precautionary principles when facing incomplete facts and causal conjectures raises the possibility of a Faustian bargain. This paper applies systems dynamics based on previously unavailable data to show how well intended precautionary policies for promoting food safety may backfire unless they are informed by quantitative cause-and-effect models of how animal antibiotics affect animal and human health. We focus on European Union and United States formulations of regulatory precaution and then analyze zoonotic infections in terms of the consequences of relying on political will to justify precautionary bans.

Precautionary principles: a jurisdiction-free framework for decision-making under risk.

Fundamental principles of precaution are legal maxims that ask for preventive actions, perhaps as contingent interim measures while relevant information about causality and harm remains unavailable, to minimize the societal impact of potentially severe or irreversible outcomes. Such principles do not explain how to make choices or how to identify what is protective when incomplete and inconsistent scientific evidence of causation characterizes the potential hazards. Rather, they entrust lower jurisdictions, such as agencies or authorities, to make current decisions while recognizing that future information can contradict the scientific basis that supported the initial decision.

Precaution, uncertainty and causation in environmental decisions.

What measures of uncertainty and what causal analysis can improve the management of potentially severe, irreversible or dreaded environmental outcomes? Environmental choices show that policies intended to be precautionary (such as adding MTBE to petrol) can cause unanticipated harm (by mobilizing benzene, a known leukemogen, in the ground water). Many environmental law principles set the boundaries of what should be done but do not provide an operational construct to answer this question. Those principles, ranging from the precautionary principle to protecting human health from a significant risk of material health impairment, do not explain how to make environmental management choices when incomplete, inconsistent and complex scientific evidence characterizes potentially adverse environmental outcomes.