Risk assessment of methylmercury based on internal exposure and fish and seafood consumption estimates in Taiwanese children.

Fish and seafood consumption is a major source of human exposure to methylmercury (MeHg). This study evaluated the potential health risk of MeHg in Taiwanese children from fish and seafood consumption using a toxicokinetic model, hazard quotients and hazard indices (HIs). Two biomonitoring programs provided an important resource for blood specimens for assessing MeHg exposure in human populations.

Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis?

The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides.

Interaction between the human mitochondrial import receptors Tom20 and Tom70 in vitro suggests a chaperone displacement mechanism.

The mitochondrial import receptor Tom70 contains a tetratricopeptide repeat (TPR) clamp domain, which allows the receptor to interact with the molecular chaperones, Hsc70/Hsp70 and Hsp90. Preprotein recognition by Tom70, a critical step to initiate import, is dependent on these cytosolic chaperones. Preproteins are subsequently released from the receptor for translocation across the outer membrane, yet the mechanism of this step is unknown.

Nanotechnology and nanomaterials: toxicology, risk assessment, and regulations.

Nanomaterials have very unique chemical and physical properties that suggest potential health hazards, but limited health and safety information exists for engineered nanomaterials. This review identifies a need for expanding efforts for addressing health and safety concerns in nanotechnology development and in nanotoxicology of engineered nanomaterials. The efforts include research to generate data for safety evaluation, toxicologic evaluation of potential human health effects, risk assessment to support risk-management decision-making, and regulations development to protect human health and the environment.

Function of cytosolic chaperones in Tom70-mediated mitochondrial import.

The great majority of mitochondrial proteins are synthesized by cytosolic ribosomes and then imported into the organelle post-translationally. The translocase of the outer membrane (TOM) is a proteinaceous machinery that contains surface receptors for preprotein recognition and also serves as the main entry gateway into mitochondria. Mitochondrial targeting requires various cytosolic factors, in particular the molecular chaperones Hsc70/Hsp70 and Hsp90.

Human mitochondrial import receptor Tom70 functions as a monomer.

The mitochondrial import receptor Tom70 (translocase of the mitochondrial outer membrane 70) interacts with chaperone-preprotein complexes through two domains: one that binds Hsp70 (heat-shock protein 70)/Hsc70 (heat-shock cognate 70) and Hsp90, and a second that binds preproteins. The oligomeric state of Tom70 has been controversial, with evidence for both monomeric and homodimeric forms. In the present paper, we report that the functional state of human Tom70 appears to be a monomer with mechanistic implications for its function in mitochondrial protein import.

Multiple 40-kDa heat-shock protein chaperones function in Tom70-dependent mitochondrial import.

Mitochondrial preproteins that are imported via the translocase of the mitochondrial outer membrane (Tom)70 receptor are complexed with cytosolic chaperones before targeting to the mitochondrial outer membrane. The adenine nucleotide transporter (ANT) follows this pathway, and its purified mature form is identical to the preprotein. Purified ANT was reconstituted with chaperones in reticulocyte lysate, and bound proteins were identified by mass spectrometry.

Framework for use of toxicity screening tools in context-based decision-making.

One of the principal applications of toxicology data is to inform risk assessments and support risk management decisions that are protective of human health. Ideally, a risk assessor would have available all of the relevant information on (a) the toxicity profile of the agent of interest; (b) its interactions with living systems; and (c) the known or projected exposure scenarios: to whom, how much, by which route(s), and how often. In practice, however, complete information is seldom available.

Hsp90 functions in the targeting and outer membrane translocation steps of Tom70-mediated mitochondrial import.

The Tom70 import receptor on the mitochondrial outer membrane specifically recognizes Hsp90 and Hsc70, a critical step for the import of mitochondrial preproteins, the targeting of which depends on these cytosolic chaperones. To analyze the role of Hsp90 in mitochondrial import, the effects of the Hsp90 inhibitors geldanamycin and novobiocin were compared. Geldanamycin occludes the N-terminal ATP-binding site of Hsp90, whereas novobiocin targets the C-terminal region of the chaperone.

Development of a health-protective drinking water level for perchlorate.

We evaluated animal and human toxicity data for perchlorate and identified reduction of thyroidal iodide uptake as the critical end point in the development of a health-protective drinking water level [also known as the public health goal (PHG)] for the chemical. This work was performed under the drinking water program of the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. For dose-response characterization, we applied benchmark-dose modeling to human data and determined a point of departure (the 95% lower confidence limit for 5% inhibition of iodide uptake) of 0.

Hot topics in toxicology.

Toxicology is facing new challenges in addressing issues that will have an impact on developing and meeting new regulatory guidance, public health protection and research directions. Efforts are made to define the exposures to potential toxicants, assess the associated risks, and reduce the uncertainties. This discussion presents an overview of the associated regulatory mandates, how various programs are approaching the current issues and the progress made, particularly here in California and also globally.