A widely-used phthalate not so different from banned cousins, rat study finds.

Jan 19, 2011

Boberg, J, S Christiansen, M Axelstad, TS Kledal, AM Vinggaard, M Dalgaard, C Nelleman and U Haas. 2010. Reproductive and behavioral effects of diisononyl phthalate (DINP) in perinatally exposed rats. Reproductive Toxicity http://dx.doi.org/10.1016/j.reprotox.2010.11.001.



Synopsis by Emily Barrett and Wendy Hessler


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sean dreilinger/flickr 
An animal study finds for the first time that another widely used phthalate affects development when exposure occurs in the womb and early life. It is also the first to show the chemical can affect brain development, too. DINP – a phthalate that is increasingly used in plastic products – caused similar changes in the male reproductive system as other types of recently banned – but more potent – phthalates.
 
The male offspring had a host of reproductive changes, while females showed signs of masculinized brain development determined through behavior tests. The results suggest that – like other phthalates – DINP should be used with caution as its anti-androgenic properties may have serious health consequences.
 
 

Context

Phthalates are a class of chemicals whith a wide variety of uses. A subgroup of them are commonly used to make plastics softer – called plasticizers – while others with different characteristics are used mainly as solvents in personal care products, cosmetics and paints. The plasticizers make hard vinyl flexible for use in flooring, medical tubing, toys, shower curtains and many other products.

Phthalates have come under intense scrutiny in recent years after studies showed that they can disrupt hormone activity in the body. Phthalates are anti-androgens. They can derail the production of male hormones – like testosterone – and change the way they act in the body.

In rodents, exposure to phthalates interferes with the normal development of organ systems that depend on hormones, like the reproductive system. Similar reproductive changes have been found in humans. Mounting evidence suggests that human brain development may be affected by phthalate exposure as well.

Some phthalates are particularly potent anti-androgens, affecting normal development even at very low doses. As a result, Europe and the United States have limited the use of the most potent phthalates – particularly in products intended for pregnant women and young children. Citing their toxic effects on the reproductive system, the European Union chose to ban three phthalates – DEHP, BBP and DBP – in toys, cosmetics, childcare products and food contact materials. Other types – including DINP – are banned in plastic products children could put in their mouths. The United States passed similar legislation to limit use of certain phthalates in toys and products that can be mouthed.

As these potent phthalates have been removed, manufacturers have routinely replaced them with purportedly less  toxic versions, such as DINP and DiDP. The two may now account for as much as 65 percent of plasticizer use in Europe, and they continue to be used in many products meant for children and pregnant women.

Given the increase in use of DINP in consumer products, human exposure levels may be high but little is known about extent of exposures and the health risks of the increased exposures to this less potent phthalate.

What did they do?

A group of Danish researchers examined how prenatal and early life exposure to DINP might affect reproductive and brain development and adult behavior in rats.

Female rats were injected daily with either 0, 300, 600, 750 or 900 milligrams of DINP per kilogram of body weight per day (mg/kg/day) from day seven of pregnancy through day 17 after they gave birth. In males, the size and testosterone production of the fetal testes were measured. After birth, the scientists measured the pups’ genitals and counted their nipples (male rats usually have none). At adulthood, the researchers measured all of the reproductive organs and determined the males’ sperm counts and quality.

By comparison, the typical exposure levels measured in people are estimated to range from about 0.01 - 1.12 mg/kg/day. The doses tested in this study are far higher, reflecting the fact that DINP is considered a weaker phthalate.

They also studied the male and female offsprings' behavior as juveniles and adults in a number of ways, including motor activity, memory and learning, and spatial abilities. All of these traits and abilities characteristically differ in male and female rats.

The scientists then analyzed whether the rats’ behavior and reproductive development differed based on whether their mothers had received DINP while pregnant and nursing.

What did they find?

Rats born to mothers who had received DINP showed a slew of changes in both their reproductive systems and their brains. High levels of DINP tended to produce the most dramatic changes, yet lower levels of exposure still produced notable effects in some cases. In general, effects started to be seen around 600 mg/kg/day.

As fetuses, the exposed male rats showed irregular testicular and sperm development. Testicular testosterone production in the fetuses was also slightly reduced with DINP exposure.

At birth, DINP-exposed male pups showed differences in the size and shape of their genitals, particularly their anogenital distance (AGD). AGD is used to measure developmental changes and is usually longer in males than females. Among males, the more DINP they had been exposed to, the shorter their AGD tended to be. Many of the male pups who received higher amounts of DINP also retained nipples after birth, unlike male pups who had not been exposed.

In adulthood, there were additional changes associated with DINP exposure. Males who had been exposed had fewer sperm that could swim properly, but more sperm overall. Behaviorally, there were no differences in motor activity. However, female pups exposed to DINP tended to perform as well as unexposed males on tests of spatial memory and much better than unexposed females.

What does it mean?

The reproductive and behavioral changes produced by DINP exposure shows that another – and less potent – phthalate can affect fetal development and produce permanent health effects in both sexes.

The results provide more evidence that the group of chemicals can act similarly and should all be used with caution in consumer products.  

This study was the first to look at changes in the brain and behavior associated with fetal DINP exposure. Although exposed males did not differ from their unexposed counterparts, exposed females showed improved performance on a spatial memory task – the Morris water maze. In fact, their performance was on par with the males, suggesting that DINP exposure in the womb may have had masculinizing effects on the females’ brains, though the mechanism for that action is not completely understood. Although this result is tantalizing, further research is needed to understand how phthalates like DINP may affect the developing female brain. 

As for males, the altered fetal testes, shortened AGD and presence of nipples in those exposed to DINP in the womb are all evidence of the chemical's ability to interfere with normal androgen hormone activity. Previous studies in rodents have shown similar effects on the reproductive system, albeit at slightly higher levels of DINP exposure.

One surprising finding was how DINP affected sperm. At high levels, DINP exposure appeared to decrease sperm quality, but it also increased overall sperm count. This suggests that DINP interferes not with sperm production but with the maturation process. It remains unknown whether these changes might impact fertility.

To date, no studies have looked at these questions of DINP exposure in humans.

Showing developmental effects from 600 mg/kg/day and beyond, DINP is far weaker than the most potent androgens, which can cause problems at doses as low as 10 mg/kg/day. However in Europe, use of DINP (and DIDP) is now three times higher than DEHP use, and human exposure to DINP has risen steadily along with that transition.

Update, 2/1/11: One study found that levels of DiNP metabolites in German students doubled from 1988 to 2003, though at their highest levels, they were still well below limits defined by the European Food Safety Authority (Wittasek et al, 2007).

As the new research shows, even a less potent phthalate can cause problems when exposure levels get high enough. The results of the new study suggest that further research on the safety of DINP and the levels of exposure in human populations are needed. Regulators may want to consider classifying DINP with the more potent phthalates in the future for their shared ability to disrupt the reproductive system.


Resources

Christiansen, S, Boberg, J, Axelstad, M, Dalgaard, M, Vingaard, AM, Metzdorff and U Haas. 2010. Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. Reproductive Toxicology 30(2):313-321.

Engel, SM, A Miodovnik, RL Canfield, C Zhu, MJ Silva, AM Calafat and MS Wolff. 2010. Prenatal phthalate exposure is associated with childhood behavior and executive function. Environmental Health Perspectives 118(4):565-71.
 

Foster, LM. 2006. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. International Journal of Andrology 29(1):140-7.
 

Gray, Jr., LE, J Ostby, J Furr, M Price, DN Veeramachaneni and L Parks. 2000. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicological Sciences 58(2):350-65.
 

Swan, SH, F Liu, M Hines, RL Kruse, C Wang, JB Redmon, A Sparks and B Weiss. 2010. Prenatal phthalate exposure and reduced masculine play in boys. International Journal of Andrology 33(2)259-69.
 

Swan, SH, KM Main, SL Stweart, RL Kruse, AM Calafat, CS Mao, JP Redmon, CL Ternand, S Sullivan and JL Teague. 2005. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environmental Health Perspectives 113(8):1056-61.
 

Wittasek, M, GA Wiesmuller, HM Koch, R Eckard, L Dobler, J Muller, J Angerer and C Schluter. 2007. International phthalate exposure over the last two decades- a retrospective human biomonitoring study. International Journal of Hygiene and Environmental Health 210(3-4):319-33.

 

 

 

 

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