Table 1.

Summary of cellular and molecular effects of MDCs with common routes of exposure, nationally recommended safe exposure levels, and estimated elimination half-lives in humans

Compound	Uses and Common Routes of Exposure		Recommended Safe Exposure Level in Humans	Cellular/Molecular Metabolic Effects	Elimination Half-life in Humans	References
Organotins (TPT, TBT)	*Biocide in marine paints, fungicide, wood preservative, PVC stabilizer *Drinking water, seafood, PVC products		0.1 mg/m3 air (OSHA/NI OSH)	General mechanisms: Activates PPARγ and RXR Whole animals: Increased weight, increased/reduced insulin levels, leptin, hepatic steatosis β-cells: Reduced GSIS, impaired Ca2+ signaling, reduced NAD(P)H and ATP, and PKA levels Insulin target cells: Increased adipogenesis	Serum half-life 3 days (POP)	[11–13,75, 76,87,103, 125]
Arsenic	*Pesticides, smelting, industrial waste *Drinking water, soil, seafood, rice, mushrooms, poultry		10 ppb (water; EPA)	General mechanisms: Oxidative stress/Unknown Whole animals: Glucose intolerance Gestational exposure: Glucose intolerance, obesity in dams β-cells: Reduced GSIS, increased ROS, impaired Ca2+ signaling, insulin granule exocytosis, insulin gene expression. Induced autophagy, apoptosis. Insulin target cells: Reduced insulin signaling, ROS, reduced hepatic glycogen	4–6 hours; 20–30 hours (methyl ated)	[14–17,30, 31,50,53, 68,104,126 ]
Cadmium	*Byproduct of mining, combustion, waste incineration *Soil, water, air; leafy vegetables, peanuts, soybeans, sunflower seeds; inhalation		0.005 mg/L (water; EPA); 5 μg/m3 per day (air; OSHA)	General mechanisms: Oxidative stress/Unknown Whole animals: Insulin resistance, increased insulin levels β-cells: Reduced GSIS, increased ROS, mitochondrial dysfunction, apoptosis, mediated by JNK Insulin target cells: Reduced GLUT4	4–38 years	[33,34,59,1–27]
Mercury		*Mining, waste incineration, manufacturing *Fish, shellfish, medical/dental procedures	2 ppb (water; EPA); 1 ppm (food; FDA); 0.1 mg/m3 (air; OSHA)	General mechanisms: Oxidative stress/Unknown β-cells: Reduced GSIS, increased ROS, PI3 kinase and Akt, induced apoptosis and necrosis.	1–3 weeks to 1–3 months (depend s on route of exposur e, chronicit y)	[35,36]
Alkylphenoli c Compounds (e.g. Octylphenol, Nonylphenol )		*Surfactants, detergents, emulsifiers *Fish, drinking water, personal care products	Undetermi ned	General mechanisms: Modulates estrogen signaling β-cells: Reduced GSIS, impaired mitochondrial structure and function. Insulin target cells: Impaired FA metabolism, reduced lipogenesis	2–3 hours (POP)	[19,128]
BPA		*Food packaging, toys, canned food liners *Ubiquitous exposure	50 mcg/kg/da y (FDA) 4 mcg/kg/da y (European Food Safety Authority)	General mechanisms: Modulates estrogen signaling Whole animals: Glucose intolerance Gestational exposure: Glucose intolerance, increased weight in both dams and offspring. β-cells: Reduced GSIS, disrupted mitochondrial structure and function, increased ROS Insulin target cells: Reduced insulin action and signaling intermediates, increased adipose inflammation (JNK, NFκB)	4–5 hours	[19,29,40,4–8, 51,52,77,7–8, 92,93,101, 102, 108]
Phthalates/P hthalate esters (e.g. DEHP, MEHP)		*Liquid plasticizers; Lend flexibility to plastics (e.g. PVC); lubricants, perfumes, cosmetics, medical tubing, wood finishes, adhesives, paints, toys, emulsifiers in food. *Ubiquitous exposure	DEHP: 6ppb (water; EPA); 5mg/m3/8 hour day (OSHA)	General mechanisms: Activates PPARγ signaling Whole animals: Insulin resistance, reduced hepatic glycogen, increased ROS. Gestational exposure: increased systemic inflammation and altered adipose development in offspring β–cells: Reduced GSIS, insulin content, increased ROS Insulin target cells: Reduced insulin signaling, glucose oxidation, increased ROS in muscle	12 hours	[32,56,57,6–9, 105]
PCBs (mix of >200 congeners)		*Plasticizers, in resins, carbonless copy paper, adhesives, paints, inks (banned 1979) *High fat food (dairy, meat, fish)	0.0005 ppm (water; EPA) 0.2–3.0 ppm (food; FDA); 0.5– 1.0 mg/m3 (air; OSHA); 6.0 ug/kg/d (total)	General mechanisms: Unknown/Varied Whole animals: Glucose intolerance β-cells: increased insulin secretion and Ca2+ signaling	6 months - >100 years (varies by exposur e; POP)	[20,129,130]
Dioxins (e.g. TCDD, PCB126)		*Byproducts of smelting, paper manufacture, herbicides and pesticides, hospital waste. *Soil, dairy, meat, seafood.	0.01- 1ng/L/day pg/kg/d (water; EPA)	General mechanisms: Activates AhR signaling, induces inflammation Whole animals: Glucose intolerance β-cells: Reduced GSIS, insulin content; increased basal insulin secretion, [Ca2+]IC Insulin target cells: Reduced insulin signaling, increased inflammation (JNK, ERK1/2), reduced hepatic glycogen	7–11years (POP)	[54,55,65, 71–74]
Perfluoroalk yl substances (e.g. PFOA, PFOS)		*Stain resistant coating in clothing, cookware, upholstery; food packaging *Food, drinking water	70 ppt (water; EPA)	General mechanisms: Modulates estrogen signaling, activates PPARα signaling Whole animals: Altered lipid metabolism, steatosis Gestational exposure: increased weight, leptin, insulin levels, glucose intolerance Insulin target cells: Increased insulin signaling/sensitivity, reduced hepatic glycogen synthesis	3–5 years	[66,106,107,131]
Tolylfluanid		*Agricultural fungicide, biocide on ships, paints *Food, water; occupational exposures in shipping and agriculture	0.1 mg/kg/day (FDA)	General mechanism: Activates GR signaling Whole animals: increased weight, adiposity, insulin resistance, glucose intolerance, altered circadian feeding patterns. Insulin target cells: reduced insulin signaling	hours - days	[49,88,90]
Atrazine		*Most widely used herbicide in the U.S.; used on corn, sorghum, sugar cane, Christmas trees, golf courses *Food, drinking water	3 μg/L (water; EPA), 5 mg/m3/shif t (OSHA)	General mechanisms: Unknown Whole animals: Increased weight, insulin resistance Insulin target cells: Reduced insulin signaling, mitochondrial toxicity, impaired FA oxidation in liver	10–11 hours	[67,112]
Particulate Matter		*Aerosol particles with diameter less than 2.5 μm; combustion associated with traffic, mining, burning coal, oil, wood *Ubiquitous; Inhalation	35 μg/m3 air daily average; 15 μg/m3 annual average.	General mechanisms: Inflammation/Unknown Whole animals: Increased visceral adiposity, insulin resistance Insulin target cells: Reduced insulin signaling, PKC activity, increased inflammation, ROS, NASH, reduced glycogen.	Unknow n	[97,98,111]