NTP-CERHR-DEHP-00, Oct 2000 Moore, 2001 EHP 109:229; Gray LE, NIEHS presentation
Most Sensitive System: Immature Male Reproductive Tract
Impacts on developing male reproductive system are at least partially independent of peroxisome proliferation, a mechanism which is related to cancer causation in rodents.
Rabbits, mice, rats, guinea pigs, ferrets all show toxic impacts. (fetal and newborn primates never studied)
Therefore, these studies are considered relevant to humans
Importance of route of exposure; species differences
DEHP converted to MEHP by intestinal lipases; less rapid conversion after IV administration
DEHP converted to MEHP in all species
MEHP eliminated largely by glucuronidation (primates); further hydrolyzed by humans before glucuronidation, by hydrolysis (rodents)
Metabolic age-related differences impacting toxicity of DEHP
Fetus and infant have reduced glucuronidation capacity compared to adult
Infants have higher gastric lipase activity than older children/adults
Children absorb more DEHP from the intestinal tract than adults
Magnitude of Neonatal Exposure (General population exposure: 0.003 – 0.030 mg/kg/day)
Neonatal Exchange Transfusion
1.8 mg/kg/exch (0.84 – 3.3) DEHP
0.3 mg/kg/tx (0.14-0.72) DEHP
ECMO (depending on circuit and assumptions)
0.0 – 140 mg/kg DEHP
Sjoberg, 1985. Eur J Clin Invest 15:430 Sjoberg, 1985. Transfusion 25:424 Karle, 1997. Crit Care Med 25:696 Levels in children with these exposures exceed the NOAEL in animal studies
NTP panel – Center for the Evaluation of Risks to Human Reproduction
"serious concern" for the possibility of adverse effects on the developing reproductive tract of male infants exposed to very high levels of DEHP that might be associated with intensive medical procedures such as those used in critically ill infants.
"concern" that, if infants and toddlers are exposed to levels of DEHP substantially higher than adults, adverse effects might occur in the developing male reproductive tract.
DEHP causes platelet aggregation and complement activation
Microemboli during ECMO or cardio-pulmonary bypass may be related to DEHP
Drug loss by binding to surface of PVC tubing or bags
Urinary levels of the DEHP metabolite, MEHP, in NICU infants Ronald Green, MD, MPH (1); Russ Hauser, MD, MPH, ScD (1); Antonia Calafat, PhD (2); Jennifer Weuve, MPH, ScD (1); Ted Schettler, MD, MPH (3); Steven Ringer, MD, PhD (4); Kenneth Huttner, MD (5); Howard Hu, MD, MPH, ScD (1,6) To assess neonatal exposure to DEHP containing medical devices encountered in the course of ICU care and measure the urinary metabolite MEHP.
HIGH exposure: umbilical vessel catheterization, endotracheal intubation, IV hyperalimentation and an indwelling gavage tube
Median and IQR of urinary MEHP, by class of DEHP exposure, adjusted for sex and institution. 0 20 40 60 80 100 120 140 160 180 200 Low Medium High MEHP ng/ml urine median DEHP exposure class 75 th percentile 25th percentile DEHP Exposure Class
1974-’75: EVA TPN bag and polyolefin platelet bag -- Baxter
1992: Citrate-softened PVC red blood cell bag -- Baxter 1980s: Polyolefin/polyester laminate bag for IV solutions -- B.Braun 1970s: Polyurethane and s ilicone umbilical vessel catheters and nasogastric tubes