11 Human risk assessment

Survey and environmental/health assessment of fluorinated substances in impregnated consumer products and impregnating agents

11.1 Toxicological summary
11.2 Tolerable daily intake

In general the knowledge about the toxicology of the perfluorinated compounds is rather sparse, and it will take some time and efforts, before we will have sufficient information for evaluation of the full impact of the present levels in humans.

11.1 Toxicological summary

PFOA and PFOS may bind to proteins in the blood and accumulate in various body tissues of exposed organisms, including in liver, kidneys, testes and brain. The half-lives of PFOS and PFOA in human blood have been estimated to about 4 years but the whole body half-life will be even longer, since the elimination of these chemicals in humans is neglible.

Although the perfluoroalkyl sulfonic acids and carboxylic acids are closely related structurally, these chemicals elicit different biological responses in vitro and in vivo. The acute lethal toxicity is moderate corresponding to a classification as harmful. PFOS is more toxic than PFOA, and the toxicity of perfluorinated chemicals increases generally with the length of the alkyl chain.

The liver is the primary target organ for perfluorinated compounds. PFOS and PFCAs cause peroxisome proliferation in the rodent liver as well as induction of various enzymes involved in lipid metabolism. PFDA with a longer alkyl chain seems even more active than PFOA. Toxic effects have been reported, such as induction of fatty liver and uncoupling of the mitochondrial respiratory chain.

Subchronic exposure of animals to PFOS may lead to significant weight loss accompanied by hepatotoxicity and reduction of serum cholesterol and thyroid hormones. PFOA and PFOS also interact with serum levels of various sex hormons, e.g. reduction of testosterone and increase of oestradiol in rats. Thus it is an endocrine disruptor.

PFOS, PFOSA, PFHxS and perfluorinated carboxylic acids with carbon chain length of 7-10 can rapidly and reversibly inhibit gap junction intercellular communication in a dose-dependent manner, and with PFDA inhibiting more than PFOA. Gap junction intercellular communication (GJIC) is the major pathway of intracellular signal transduction, and it is thus important for normal cell growth and function. Defects in this communication may lead to teratogenesis, neuropathy, infertility, diabetes, autoimmune disorders, cancer, and other diseases.

PFOA and PFOS also affect the serum levels of various hormones, i.e. reducing testosterone, and increasing estradiol in rats. Thus it acts as an endocrine disruptor.

Although the fluorinated chemicals do not seem to be mutagenic, PFOA induces testis tumors and PFOS and EtFOSE induce liver cancer in experimental animals. USEPA classifies PFOA as a carcinogen in animals.

PFOS causes developmental effects including reduction of foetal weight, cleft palate, oedema, delayed ossification of bones, and cardiac abnormalities. However, the structural abnormalities were found in the highest PFOS dose groups, where significant reductions of weight gain and food consumption were also observed in the pregnant dams. Thus the relevance of these effects may be questioned. PFOA causes reduction of foetal weight. Other PFAS (PFBS and PFHxS) have neither a significant effect on reproduction nor on development, even at high doses.

The experience from the working environment has not indicated any important adverse health effects among exposed workers, besides a retrospective cohort mortality study of a perfluorooctane sulfonyl fluoride (PFOSF) production workforce, which reported an excess of bladder cancer at high-exposure jobs.

The risk characterisation for the general population shows according to Butenhoff et al. (2004) a sufficient margin of exposure and safety. This assessment was, however, based on animal data regarding liver weight increase and Leydig cell adenoma, which may be irrelevant for humans.

Two recent human studies link prenatal exposure to perfluorinated compounds to lower birth weight (Apelberg et al. 2007b; Fei et al. 2007)

11.2 Tolerable daily intake

The Committee on Toxicity (2006ab) in the U.K. has recently performed a risk assessment of PFOA and PFOS:

The lowest NOAEL for PFOA found was 0.06 mg/kg bw/d for increased liver weight in rats in a 13-week study. However, a five times higher level of 0.3 mg/kg bw/d and a uncertainty factor of 100 to allow for inter- and intra-species variation was used for deriving the TDI for PFOA of 3 mg/kg bw/d. That was compared with an estimated food intake of up to 0.1 mg/kg bw/d for adults and 0.3 mg/kg bw/d for toddlers.
The lowest NOAEL for PFOS found was 0.03 mg/kg bw/d for decreased T3 levels in a 26-week monkey study. It was used to propose a provisionally TDI for PFOS of 0.3 mg/kg bw/d using an uncertainty factor of 100 to allow for inter- and intra-species variations. The food intake of PFOS in UK was estimated to max. 0.2 mg/kg bw/d in adults and 0.5 mg/kg bw/d in 1.5-2.5 year olds, thus for some small children the TDI is exceeded.

There are several aspects in these risk assessments which may be questioned:

The lowest NOAEL for PFOA was not used.
The durations of the animal experiments, from which data used were collected, were 3-6 months. Life-time bioassays are likely to generate lower NOAELs. Normally, a further uncertainty factor of 10 is used when using sub-chronic instead of chronic toxicity studies. This has not been done in the UK risk assessment.
The conservative threshold approach is used for PFOA, although PFOA is considered to be an animal carcinogen by US EPA.
The uncertainty factor of 100 applied in the estimations above seems to be very conservative, because the half-lives of these chemicals in human blood are 20-100 times longer than half-lives in rodents, and there are other differences to take into account. The fact that the renal clearances of PFOA and PFOS are insignificant in humans, contrary to a large active excretion in experimental animals (Harada et al. 2005a) means that these chemicals in humans leaves the blood by redistribution to internal organs and not by elimination from the body. This increases the internal exposure time in critical organs considerable and makes risk assessment of perfluorinated chemicals based on animal experiments very arbitrary and unreliable.
The referred maximum food intake in the U.K. may not be typically for other countries and the time trend is not known.
People are exposed to these chemicals and their precursors from other sources than food. Some studies have shown that direct product exposure, indoor air and dust may be more important.