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Survey and health assessment of chemical substances in jewelleries

6 Health assessment of lead, cadmium, copper and nickel

• 6.1 Lead
  • 6.1.1 Occurrence and use
  • 6.1.2 Identification
  • 6.1.3 Physical and chemical properties
  • 6.1.4 Oral absorption
  • 6.1.5 Dermal absorption
  • 6.1.6 Distribution
  • 6.1.7 Acute toxicity
  • 6.1.8 Local irritation and allergy
  • 6.1.9 Long-lasting, repeated effect and gene-damaging effects
  • 6.1.10 Tolerable daily intake - TDI
• 6.2 Cadmium
  • 6.2.1 Occurrence and use
  • 6.2.2 Identification
  • 6.2.3 Physical and chemical properties
  • 6.2.4 Oral absorption
  • 6.2.5 Dermal absorption
  • 6.2.6 Distribution
  • 6.2.7 Acute toxicity
  • 6.2.8 Local irritation and allergy
  • 6.2.9 Long-lasting, repeated effect and gene-damaging effects
  • 6.2.10 Tolerable daily intake - TDI
• 6.3 Copper
  • 6.3.1 Occurrence and use
  • 6.3.2 Identification
  • 6.3.3 Physical and chemical properties
  • 6.3.4 Oral absorption
  • 6.3.5 Dermal absorption
  • 6.3.6 Distribution
  • 6.3.7 Local irritation and allergy
  • 6.3.8 Acute toxicity
  • 6.3.9 Long-lasting, repeated effect and gene-damaging effects
  • 6.3.10 Tolerable daily intake - TDI
• 6.4 Nickel
  • 6.4.1 Occurrence and use
  • 6.4.2 Identification
  • 6.4.3 Physical and chemical properties
  • 6.4.4 Oral absorption
  • 6.4.5 Dermal absorption
  • 6.4.6 Distribution
  • 6.4.7 Local irritation and allergy
  • 6.4.8 Acute toxicity
  • 6.4.9 Long-lasting, repeated effect and gene-damaging effects
  • 6.4.10 Tolerable daily intake - TDI

The selection of metals for health assessment was based on the results from the migration analysis. Thus, only the 4 metals which migrated in a concentration above the detection limit were selected for exposure and health assessment.

The chosen metals are presented in the table below.

Table 6-1: Selected metals for exposure and health assessment.

In the following health assessment it is assumed that metal in contact with sweat primarily forms metal chlorides. Thus, TDI values, dermal and oral absorption rates are, as far as possible, based on information related to metal chlorides (or the metal itself) – or alternatively studies regarding inorganic metal compounds.

The argumentation for this assumption is partly based on a study by Menné (1994) quoted from ATSDR (2005a), which claims that nickel alloys that are in contact with the skin, form nickel chlorides. The argumentation is likewise based on a risk assessment of nickel performed by the Danish Environmental Protection Agency in 2005 (Andersen et al., 2005a). According to this risk assessment a corrosion of metal surfaces takes place when the metal surfaces are in close contact to skin/sweat. The corrosion is caused by the constituents of sweat. The primary constituents in sweat are chlorides (average value: 0.44-1.44 g/L), natrium (0.33-1.28 g/L), kalium (0.29-0.39 g/L), urea (0.26-1.22 g/L), ammonia (0.06-0.11 g/L), amino acids (0.48-1.4 g/L) and lactic acid (0.4-3.6 g/L). The corrosion of metal in sweat is according to the risk assessment primarily dependent on the chloride and oxygen content, which in part supports the assumption of metal chlorides being the primary component formed in sweat.

The solution used for simulating saliva contains, besides the constituents mentioned above, also natrium sulphate. However, natrium sulphate is not expected to form organic compounds, thus it is assumed that the primary metal compound of interest (which will form in saliva, which is in contact with metal jewellery) likewise is metal chloride.

However, it is possible that other forms of metal compounds can be formed in sweat (or saliva), compounds that might have a significant impact on the total absorption of metals. However, it is not possible within the scope of this project to clarify exactly which kind of metal compounds that can be formed (besides metal chlorides), since the literature on this subject is very limited. In theory, studies (including laboratories tests) should be performed in order to clarify exactly which compounds are formed.

A massive amount of information is available regarding the health effects associated with the four metals. Thus, it is stressed that the health assessments carried out below are based on extracts of the most relevant available information for this project.

The primary goal of the health assessments here is to locate a NOAEL (No Observed Adverse Effect Level) or TDI (Tolerable Daily Intake) value related to the critical effect of the metal. The term “critical effect” relates to the health effect that occurs at the lowest exposure of the substance. NOAEL or TDI values related to this critical value are used subsequently along with an exposure calculation in order to clarify whether the amount of metal that humans are exposed to by carrying/sucking jewelleries constitutes a health risk. During the exposure calculation the identified dermal and oral absorption rates related to the four metals are used. Here it should be mentioned, that it is assumed that metal absorbed through the skin causes the same toxic effects in the body, as metal ingested through the mouth.

6.1 Lead

6.1.1 Occurrence and use

Lead is a heavy and soft metal which exists naturally in the earth’s crust, however, in the form of lead compounds. Lead is corrosion-resistant, easy to mould, acid-resistant, chemically stable in water, air and soil, and can be combined with other metals in the form of alloys. Due to these qualities lead and lead alloys are used worldwide for among other things pipes, batteries, ammunition, cables and panels for protection against X-raying. The primary use of lead today is in batteries for use in cars and other vehicles (ATSDR, 2005).

In addition to this lead is also used in the production of jewelleries. The reason for this is probably that lead is a relatively cheap metal, which besides being corrosion-resistant, is easy to mould. Furthermore, a content of lead can help make the piece of jewellery heavier and thereby increase the similarity to precious jewellery. Lead weighs almost the same as gold. The use of lead in jewellery could also be caused by the fact that lead can affect the surface of the jewellery in such a way that it looks a bit like precious metal.

Prior to the commencement of the statutory order regarding lead the lead consumption was estimated. In Denmark the total consumption of lead (in finished products) in 2000 was estimated to be between 14,900 and 19,000 tonnes. The consumption was divided between metallic lead (91%), chemical compounds (9%) and “supporting substance” in other goods (0.06%) (Lassen et al., 2004). Worldwide approx. 7 mio. tonnes of lead are produced each year, of which half originates from recycled metal waste^[1]. According to WHO (2003) more than 80% of the daily intake of lead originates from food, soil and dust.

6.1.2 Identification

6.1.3 Physical and chemical properties

6.1.4 Oral absorption

Lead taken up through food or beverages is absorbed differently depending on when the person last had a meal. Experiments have shown that adults who had just eaten a meal only absorbed 6% of the ingested amount of lead, while adults who had not eaten for a period of 24 hours absorbed between 60 and 80% of the ingested amount of lead. Typically, children absorb 50% of the ingested amount of lead (ATSDR, 2005).

For use in this project an oral absorption rate of lead compounds is set at 50%  - based on the value measured for children. This value is assumed to be a representative value for oral absorption in adults as well, since this value lies between the value for lead absorption with prior food ingestion (6%) and lead absorption without prior food ingestion (60-80%) at adults.

6.1.5 Dermal absorption

Dermal absorption of inorganic lead compounds is generally assumed to be lower than absorption via inhalation or food. Experiments with application of cosmetic products containing ²⁰³Pb-marked lead acetate (0.12 mg Pb in 0.1 ml or 0.18 mg Pb in 0.1 g lotion) on 8 adults for a period of 12 hours showed absorption of = 0.3%, based on²⁰³Pb measurements in urine and blood in the entire body. It was assumed that by normal use (of the lotions) only 0.06% would be absorbed (Moore et al., 1980 in ATSDR, 2005).

Other experiments (3 non-specified persons, period of 24 hours) with dermal exposure of 5 mg Pb as lead nitrate or lead acetate resulted in less than 1% absorption. The same study showed no absorption of lead carbonate (ATSDR, 2005).

Results from animal experiments have shown similar low absorption rates (lead naphthenate: 0.17%; lead nitrate: 0.03%; lead stearate: 0.006%; lead sulphate: 0.0006%, lead oxide: 0.005% and lead-powder: 0.002%) (Bress and Bidanset, 1991 in ATSDR, 2005).

Based on the above mentioned information a dermal absorption rate of lead (in sweat) of 0.06% is used in this project.

6.1.6 Distribution

Following oral absorption the lead is transported via the red blood cells (where the lead is bound to haemoglobin) from the intestines to the different organs (WHO, 2003). At first the lead ends up in organs such as liver, kidney, lungs, brain, spleen, muscles and heart. After several weeks most of the lead ends up in bones and teeth (ATSDR, 2005). The half-life of lead in blood and “soft tissue” is in adults 20-30 days (IARC, 2006), while it in bones is approx. 30 years (Baars et al., 2001).

In adults approx. 94% of the total amount of accumulated lead ends up in bones and teeth, while in children 73% of the accumulated lead ends up in bones (ATSDR, 2005). Lead can be released from the bones in situations where the person suffers from calcium deficiency or osteoporosis (WHO, 2000). Lead is easily transferred to foetuses during pregnancy (Baars et al., 2001). Inorganic lead is not converted in the body. Unabsorbed lead, which is absorbed via the food, is released through the faeces, while absorbed lead, which is not retained, is released via the kidneys (WHO, 2003).

Children, who ingest more than 5 µg lead per kilo body weight per day, will retain (netto) 32% of the intake, while children who ingest less than 4 µg lead per kilo body weight per day will excrete more than what is taken in (WHO, 2003).

6.1.7 Acute toxicity

Lead affects pretty much all organs in the body, and serious lead poisoning can cause death. This was confirmed by the death of a 4-year old boy, who by accident had swallowed a heart-shaped metal charm (that came along free of charge by purchasing a pair of shoes). The metal charm showed to contain 99% of lead. At the time of death the boy had a blood lead concentration (in short PbB) of 180 µg/dL (Berg et al., 2006).

Obvious signs of acute lead poisoning involve dullness, restlessness, irritation, poor power of concentration, headache, vibrations in muscles, stomach cramps, kidney injuries, hallucinations and loss of memory. These effects can occur at PbB levels of 100-120 µg/dL in adults and 80-100 µg/dL in children (WHO, 2003).

Though, health effects are generally not observed after single doses and no LD₅₀ value related to lead and lead compounds (in humans) are located in the literature (WHO, 2000).

The lowest observed values related to acute deathly oral doses are found in animal studies using lead acetate, lead chlorate, lead nitrate, lead oelate, lead oxide and lead sulphate. The result varied from 300 to 4000 mg per kilo bodyweight. The large span in the result was due to varying absorption of the different lead salts as well as differences in the exposure (WHO, 2000).

6.1.8 Local irritation and allergy

According to IUCLID (2000) no data is available regarding the ability of lead to cause local irritation. Nonetheless, lead(II) oxide (PbO) is known to be moderate skin irritating at exposure levels of 100 mg over a period of 24 hours (IUCLID, 2000a).

According to IUCLID (2000) no data is apparently available regarding the potential allergic qualities related to lead.

6.1.9 Long-lasting, repeated effect and gene-damaging effects

Lead is a chronic accumulative poison. Signs of chronic lead poisoning includes among other things tiredness, sleeplessness, irritation, headache, pains in the joints and problems related to the stomach- and intestinal system. These effects can occur in adults having a PbB between 50-80 µg/dL (WHO, 2003). Lead poisoning in children can additionally cause reduced growth and delayed sexual maturation (ATSDR, 2005).

A number of studies exist, which deal with health related effects of lead and lead compounds. Some of these studies are described in ATSDR (2005) and WHO (2003). Below a segment of these is presented, though focusing on studies which have shown health related effects at the lowest measured concentration of lead in the body.

Neurological effects have been reported in workers having a PbB at 40-80 µg/dL. The neurological effects included among other things uneasiness, forgetfulness, irritation, dullness, headache, tiredness, impotence, decreased libido, dizziness and weakness (ATSDR, 2005).

The kidney function seems to be the biological function, which according to ATSDR (2005) is affected at the lowest measured PbB. Two studies have shown effects related to this function at PbB < 10 µg/dL. Another typical symptom related to chronic lead poisoning is anaemia. At a blood lead concentration < 10 µg/dL an enzyme involved in the synthesis of red blood cells has been seen inhibited. Decreased neurological activity has been reported in children and elderly people with a PbB < 10 µg/dL and according to WHO (2003) a study (from 1987) examining 500 schoolchildren (age 6-9 years) showed a small, but significant correlation between PbB and reduced intelligence test, reading and speaking abilities. The dose-response relationship was between 5.6 – 22.1 µg/dL. However, another similar study has not been able to reproduce the results (WHO, 2003).

Regarding reproductive effects a relation between PbB> 20 µg/dL and an increased chance of abortion and stillborn babies have been proven (WHO, 2000). EPA (1986a) quoted from ATSDR (2005) has furthermore identified a LOAEL value of 60-100 µg/dL related to colic in children as a result of lead poisoning.

Generally inorganic lead compounds are according to IARC (2006) “potentially cancer-causing in humans” (Group 2A), while organic lead compounds are not classified as to their cancer-causing ability in humans.

6.1.10 Tolerable daily intake - TDI

Baars et al. (2001) has through a review of new literature since 1991 not been able to find arguments for altering the TDI value of 25 µg/kg bw/week (based on effects at a PbB at 10 µg/dL), which in 1995 was found still to be valid by WHO (1995) – both regarding adults as well as children. Baars et al. (2001) calculated, based on this TDI value, a tolerable daily intake (TDI) of lead to be 3.6 µg/kg bw/day.

ENHIS (European Environment and Health Information system) presents on their homepage² (updated 14 January 2008) likewise a TDI value related to lead of 25 µg/kg bw/week.

However, WHO (2003) describes a number of studies, which indicate a possible correlation between reduced IQ and a PbB of < 10 µg/dL (5.6 µg/dL). It is, however, not possible based on these studies to calculate a new NOAEL value, since there is not enough information available. However, to take into consideration these new results, which indicate that the TDI value of 3.6 µg/kg bw/day (which is based on effects at a PbB of 10 µg/dL), might be too high, it is chosen to divide the TDI value by two. Thus, a TDI value of 1.8 µg/kg bw/day emerges, which in this project is chosen as the valid TDI value.

Adjustment of TDI values due to background exposure

TDI values shall be seen as the total amount of substance a human can tolerate to take in (ingest) on a daily basis (throughout an entire lifetime) without experiencing health related effects, cf.^[2]. However, when dealing with tolerable daily intake of lead, it is important to take into consideration the amount of lead that the population already is exposed to (for instance lead from water, food and air).

Background exposure of lead via food and beverages in Denmark

According to a report published by the Danish Veterinary and Food Administration (Fromberg et al., 2005) the background exposure from food etc. in Denmark is in average 19 µg/day. The numbers in the report are based on studies regarding content of metals in 96 foods in Denmark during the period 1998-2003 (Fromberg et al., 2005), as well as numbers regarding the average food intake in Denmark during the period 2000-2002 (Andersen et al., 2002). The numbers given by Fromberg et al. (2005) include exposure via beverages and tap water.

A recalculation of the average value of 19 µg/day to intake per kilo bodyweight (by the use of TGD’s reference weight related to women (60 kg), since women are assumed to be those, who most often wear jewellery) gives an average daily intake of lead for adults of (19/60) 0.317 µg/kg bw/day. Fromberg et al. (2005) also states numbers for the average intake of lead by children in the age 4-6 years. According to these numbers a child of 4-6 years take in – in average – 9.7 µg lead/day. According to netdoktor.dk^[3] a child of 5 years weighs 19 kg (both girls and boys). However, netdoktor.dk informs that children, since the study of which the numbers were based upon was performed, have gotten heavier. It is therefore assumed that a 5 year old child in Denmark weighs 20 kg. This number also correlates with the reference weight, which according to the TGD is supposed to be used for children. With these data in mind, the average background exposure of lead (through food) in children in Denmark is (9.7/20) 0.485 µg/kg bw/day.

Fromberg et al. (2005) also states the background exposure in terms of 95-percentiles (i.e. a value for the maximum level of which 95% of the population is exposed to). If these values are used a background exposure for adults of (31/60) 0.517 µg/kg bw/day is achieved. For children the background exposure would be (15.4/20) 0.77 µg/kg bw/day.

Background exposure of lead via air in Denmark

According to the report “The Danish Air Quality Monitoring Programme” from 2006 (performed by the National Environmental Research Institute) (Kemp et al., 2007) the highest measured average value for content of lead in the air in Denmark was 9.1 ng/ m³ (value measured in Copenhagen, on the street “H.C. Andersen’s Boulevard”). In order to choose a conservative approach this value is used to estimate the amount of lead, that humans in Denmark are assumed to inhale through the air.

According to the TGD an adult inhales 18 m³ of air per 24 hours, while a child of 20 kg (5 years) inhales 11 m³ per 24 hours. Thus, an adult (60 kg) inhales (18m³×9.1ng/m³/1000) 0.1638 µg lead per day. Converted into per kilo bodyweight (60 kg) the number is 0.003 µg/kg bw/dag. And a child (20 kg) would take in (11m³×9.1ng/m³/1000) 0.1001 µg lead per day, which converted into per kilo bodyweight gives a figure of 0.005 µg/kg bw/day related to intake of lead through the air.

Total background exposure

Since the TDI value, as mentioned earlier, represents the maximum amount of substance a person can take in per day (through their entire life) without causing health related effects, the TDI value is deducted the above mentioned values for background exposure. Thereby a number “Margin to TDI value” arises. This number represents the “extra amount” of lead, which a human can have on a daily basis (besides what they are exposed to via food, beverages and air) without experiencing health related effects. During the risk assessment this value is compared with what humans are exposed to by wearing or sucking the jewelleries, which are examined in this project. If the exposure exceeds this “Margin to TDI value” there will be a health related risk by wearing and/or sucking the jewelleries.

Table 6-2: Background exposure of lead in Denmark and “Margin to TDI value” (µg/kg bw/day).

NB: The 95-percentile relates to the numbers representing background exposure via food and beverages (including tap water). * The value represents an average value from the monitoring station in Denmark, which showed the highest average in 2006.

If people live in surroundings where they are exposed to higher background levels than the ones mentioned above, the health risk by using the examined jewelleries in this project will be underestimated.

6.2 Cadmium

6.2.1 Occurrence and use

Cadmium is a soft silver-white metal that occurs naturally in the surface of the earth. It is often found as cadmium oxide, cadmium sulphite and cadmium carbonate in zinc, lead and copper mineral veins. Furthermore, cadmium is found as cadmium chloride and cadmium sulphite compounds. Both of them are water-soluble (ATSDR, 1999).

Cadmium, cadmium alloys and cadmium compounds are used worldwide in a long range of products. Five main categories are nickel-cadmium batteries, pigments primarily used in plastic, ceramics and glass, stabiliser in PVC, surface cover on steel, few non-iron metals and components in various alloys (ATSDR, 1999). Furthermore, cadmium is often used as solder metals because the content of cadmium promotes the solder properties – the solder metal floats well and easily into the small cracks when there is a content of cadmium. Furthermore cadmium can be a naturally found metal when silver is extracted and this is why it traditionally/historically occurs in silver alloys from some parts of the world. Because of this jewelleries made of so-called ”Indian silver” often have a high content of cadmium. Cadmium is also cheaper than precious metals.

The use of cadmium in Denmark in 1996 was estimated to be 43–71 tons (Environmental project no. 557, 2000).

6.2.2 Identification

6.2.3 Physical and chemical properties

6.2.4 Oral absorption

An experiment with absorption of cadmium through food (presumably single dosages) showed an absorption of 6% after 20 days. The experiment was performed on 5 adults (Rahola et al., 1973 in ATSDR, 1999). Similar results were achieved in an experiment with 14 adults who absorbed 4.6% cadmium in average from a cadmium chloride solution (administered together with food) after 1-2 weeks where a faecal marker was extracted (McLellan et al., 1978 in ATSDR, 1999). According to WHO (2004) an experiment has been reported (from 1987), where 3-7% cadmium has been absorbed in healthy adults while 15-20% was absorbed in humans suffering from iron deficiency.

As the experiment above indicates the content of iron in the body affects the absorption of cadmium. Experiments using humans with low iron deposits have shown an absorption of 8.9% while humans with adequate iron deposits had an absorption of 2.3% (Flanagen et al., 1978 in ATSDR, 1999).

The EU risk assessment of cadmium from 2007 concludes that the oral absorption of CdO/Cd metal generally is lower than 5%, but only when iron deposits are adequate. When iron deposits are low (typically for women including pregnant women), the oral absorption can rise to 5-10%.

Based on the information above an oral absorption of cadmium for use in this project is set at 8.9%. This value has been chosen because it cannot be ruled out that a part of the Danish population suffers from iron deficiency, among these especially women (who often are those wearing jewellery). The value of 8.9% has been chosen as opposed to the 10% mentioned as maximum absorption in the EU risk assessment, because the experiments that the 10% are based on are not described in details. In addition, the value of 8.9% represents an experiment performed with cadmium chloride, which is seen as relevant for this project.

6.2.5 Dermal absorption

A study (Wester et al., 1992) investigated dermal absorption of cadmium by using in vitro skin cells from humans. Radioactive cadmium (¹⁰⁹CdCl₂) was poured over the skin for a period of 16 hours. The result was that 0.1-0.6% of the cadmium was absorbed into the plasma.

Experiments with dermal cadmium absorption in animals showed an absorption (measured in liver and kidneys) of 0.4–0.61% two weeks after ended treatment. The experiment involved a rabbit that was dosed with CdCl₂ on the skin using a 1% aqueous solution (6.1 mg Cd) or 2% ointment (12.2 mg Cd). The area used on the rabbit consisted of a 10 cm² shaved area. The rabbit was treated 5 times during a period of 3 weeks. Only the content in the kidneys and liver was measured which means that the total skin absorption could have been higher (ATSDR, 1999).

A similar experiment with a hairless mouse, which was treated with CdCl₂ on the skin using a 2% ointment (containing 0.61 mg Cd) showed an absorption of cadmium in kidneys and liver of between 0.2 and 0.87% (ATSDR, 1999).

A study described in EU's risk assessment of cadmium from 2007 shows a dermal absorption of cadmium through human skin of 0.6% (absorption into plasma). This study describes the highest measured value for dermal absorption through human skin (sofar identified in this project) and is therefore chosen as valid for dermal absorption of cadmium in this project.

6.2.6 Distribution

Most of the absorbed cadmium ends up in liver and kidneys and stays there for several years. A small amount of the absorbed cadmium will, though, leave the body slowly through the urine and faeces (ATSDR, 1999). The way cadmium is absorbed does not influence the distribution in the body in a degree worth mentioning.

Absorbed cadmium is transported to other parts of the body through the blood. Cadmium will in the body bind to metal-lothioneine where after it will be released to the urine through the kidneys. From the urine it will be re-absorbed. After the re-absorption the bonding to metal-lothioneine is broken and the free cadmium stimulates the production of metal-lothioneine, which again bind cadmium in the kidney cells – thereby preventing the toxic effect related to the free cadmium ion. If the production of metal lothioneine cannot follow the result is damage on the kidney cells, which can be detected by an increased release of proteins (with a low molecular weight) in the urine (Friberg et al., 1986 in WHO, 2004).

In humans the average cadmium concentration in liver and kidneys is equal to nil at birth but increases gradually to around 40-50 mg/kg (w/w) in the kidneys at the age of 50-60 and 1-2 mg/kg (w/w) in the liver at the age of 20-25 (Baars et al., 2001). After ”normal” exposure of cadmium from background levels approximately 50% of the body’s total amount of cadmium is found in the kidneys, approximately 15% in the liver and around 20% in the muscles. Half life periods for cadmium in kidneys and liver are estimated to 6-38 years and 4-19 years respectively (Baars et al., 2001).

6.2.7 Acute toxicity

Cadmium compounds have a moderate acute toxic effect but oral absorption of large amounts of cadmium gives a massive loss of liquid, liquid accumulations, extensive destruction of organs and finally death (Buckler et al., 1986; Wisniewska-Knypl et al., 1971 in ATSDR, 1999). According to a study by Buckler et al. (1986) a 17 year old girl died (unknown weight) 30 hours after having absorbed 150 grams of cadmium chloride.

Oral LD₅₀ values for mice and rats lie between 60 and 5000 mg/kg bw. The most significant effects are desquamation of the tissue in the stomach-intestine canal, destruction of the mucous membrane in the stomach-intestine canal and nutrition disruptions in the liver, heart and kidneys (Krajnc et al., 1987 in WHO, 2004). The lowest acute oral LD₅₀ value resulting in death (for two rats) in a study with 20 rats, was 15.3 mg/kg (Borzelleca et al., 1989 in ATSDR, 1999).

6.2.8 Local irritation and allergy

Cadmium chloride can induce sting and first degree burns on the skin at short time exposure (HSDB).

According to ATSDR (1999) dermal exposure of cadmium does not seem to have any effect on the immune system. Routine ”plaster-tests” among dermatitis and patients with Eczema showed skin irritation at exposure with a 3% cadmium chloride solution. However no signs of allergenic reactions were found at an exposure with a 1% solution on humans who had not been exposed to cadmium previously (Rudzki et al., 1988; Wahlberg, 1977 in ATSDR, 1999).

A study with guinea pigs showed no signs of allergenic reactions after intra dermal or topical exposure of cadmium chloride in concentrations up to 0.5% (ATSDR, 1999).

6.2.9 Long-lasting, repeated effect and gene-damaging effects

Exposure of cadmium/cadmium compounds includes a number of health damaging effects as described in ATSDR (1999). Several studies have indicated that oral absorption of cadmium in high concentrations induces serious irritation of the ingestion system. The typical symptoms include nausea, vomiting, saliva secretion, stomach pains, cramps and diarrhoea. There are no precise values for the dosage available but a content of 16 mg/L cadmium in lemonade has shown to induce stomach problems for children. If an absorption of 0.15 litre and a body weight of 35 kg are assumed, a dosage promoting vomiting is 0.07 mg/kg (ATSDR, 1999).

Several studies have indicated that the kidneys are the organ that is most sensitive to long-term oral exposure of cadmium. The critical (irreversible) effect is kidney damage characterized by enhanced excretion of proteins with low molecular weight in the urine. A study has shown effects at a concentration of cadmium of 50 µg/g wet weight in the renal cortex. The study indicated in a similar way that the critical concentration can be lower for the general population than for people working with cadmium (Buchet et al., 1990 in ATSDR, 1999).

According to Baars et al. (2001) new experiments indicate that the lowest cadmium concentration in the kidneys, which induces kidney damage at approximately 4% of the general population is about 50 mg/kg. This is a level that can be expected to be reached after 40-50 years absorption of 50 µg cadmium per day (corresponding to 1 µg/kg bw/day). This value was established by, among others, the WHO in 1991 as an oral human-toxicological MPR value (maximum acceptable risk) for cadmium, based on kidney damage as the most sensitive effect after oral absorption of cadmium.

However, Baars et al. (2001) claimed that because this oral absorption of 1 µg/kg bw/day results in effects in 4% of the population a TDI value should be set lower. Thus, they used an additional safety factor of 2 and reached a TDI value of 0.5 µg/kg bw/day (Baars et al., 2001).

However, ATSDR (1999) reported an even lower TDI value of 0.2 µg/kg/day related to chronic effects on the kidneys (abnormal concentration in the urine of ß₂-microglobuline). The study underlying this value is a study of Nogawa et al. (1989) which includes 1850 cadmium-exposed humans and 294 non-exposed humans. The study showed a NOAEL value of 0.0021 mg/kg/day. ATSDR (1999) used a safety factor of 10 for variation between humans and reached a TDI value of 0.2 µg/kg bw/day.

According to IARC (1997a) cadmium and cadmium compounds are carcinogenic for humans.

6.2.10 Tolerable daily intake - TDI

ATSDR (1999) states an TDI value of 0.2 µg/kg bw/day, which is the lowest value reported in ATSDR.

However, FAO/WHO´s food committee JECFA has as late as 2005 re-assessed cadmium and established a PTWI (provisory tolerable weekly intake) of 0.007 mg/kg bw, which corresponds to 1 µg/kg bw/day. This value is also given at ENHIS’s (European Environment and Health Information System) homepage (updated 14 January 2008).

The value is also used by the food institute in Denmark. The Chemical Agency in Sweden ”Kemi” also uses this PTWI value but states that the value represents an “effect level” and judge that it should be considered to lower the value by using an additional safety factor.

Due to this an additional safety factor of 2 is used in this project resulting in a TDI value of 0.5 µg/kg bw/day.

Adjustment of TDI values due to background exposure

As already mentioned TDI values shall be seen as the amount of substance that humans can tolerate to take in on a daily basis (throughout their entire life) without causing health related effects. It is here important to take into consideration the amount of cadmium that the population already is exposed to (via food, smoking, water and air).

Background exposure of cadmium via food and beverages in Denmark

According to Fromberg et al. (2005) the background exposure of cadmium from food and beverages in Denmark is in average 10 µg/day for adults. If this value is converted to absorption per kilo body weight (based on women’s weight according to TGD (60kg)) an average absorption of cadmium for adults will be (10/60) 0.167 µg/kg bw/day. Children are exposed to 7.7 µg cadmium in average per day according to Fromberg et al. (2005), which converted will result in a background exposure of (7.7/20) 0.385 µg/kg bw/day.

Fromberg et al. (2005) also states the background exposure in 95-percentiles (i.e. a value for the maximum level of which 95% of the population is exposed to). If these values are used a background exposure is obtained for adults of (17/60) 0.283 µg/kg bw/day and for children of (11.9/20) 0.595 µg/kg bw/day.

Background exposure of cadmium via air in Denmark

According to the report ”The Danish Air Quality Monitoring Programme” from 2006 (prepared by National Environmental Research Institute) (Kemp et al., 2007) the highest measured average value for the content of cadmium in the air in Denmark was <2.4 ng/m³ (the value was measured on “Banegårdsgade” in Aarhus). In order to choose a conservative approach this value is used to estimate the amount of cadmium, which an adult in Denmark is expected to inhale via the air.

According to the TDG an adult inhales 18 m³ air during a period of 24 hours, while a 5 year old child (20 kg) inhales 11 m³ during the 24 hours. This means that an adult human (60 kg) absorbs (18m³×2.4ng/m³/1000) 0.0432 µg cadmium per day, which corresponds to 0.001 µg/kg bw/day. Children (20 kg) absorb (11 m³×2.4ng/m³/1000) 0.0264 µg cadmium per day, which corresponds to an absorption of cadmium through the air of 0.001 µg/kg bw/day for children.

Background exposure of cadmium via smoking

According to Baars et al. (2001) a human smoking 20 cigarettes a day absorbs 1-2 µg cadmium a day. Converted into absorption per kilo body weight this corresponds to (2/60) 0.033 µg cadmium/kg bw/day. The data is from 1992 but is assumed still to be valid because the content of cadmium in cigarettes is not assumed to have changed significantly since 1992. Children of 4-6 years of age are not expected to smoke.

Total background exposure

Because the TDI value as mentioned previously represents the amount of substance that a human as maximum can take in per day (during a life time) without causing health related effects, the TDI value is subtracted the above mentioned data for background exposure. Thereby a number is reached (”Margin to TDI value”) representing the ”extra amount” of cadmium that a human can take in on a daily basis (besides what a human is exposed to through food, beverages, air (and smoking)) without experiencing health damaging effects. This value is compared in the risk assessment with the amount that humans are exposed to by wearing or sucking the jewellery examined in this project.

Table 6-3: Background exposure of cadmium in Denmark and “Margin to TDI value” (µg/kg bw/day).

NB: The 95-percentile relates to the data for background exposure via food and beverages (including tap water). *The value for air is an average from the monitoring station in Denmark that has shown the highest average. For smokers the total background exposure must be added a value of 0.033 (based on a consumption of 20 cigarettes per day).

As it is shown in the table it seems that the 5% of the Danish children, which are being exposed to the highest background exposure, absorbs an amount of cadmium on a daily basis that is higher than the tolerable daily dosage.

In addition it must be mentioned that adult smokers absorb 0.033 µg cadmium extra per kilo body weight per day. Because this exposure is of own choosing it is not included in the calculations of exposure.

If people live in areas where they are exposed to higher background concentrations than those described above, the health risk when using the jewelleries examined in this project will be underestimated.

6.3 Copper

6.3.1 Occurrence and use

Copper is a reddish metal, which naturally occur in stone, soil, water, sediment and (in low concentrations) in the air. Furthermore, copper is found in a number of different minerals like, among others, chalcocite (Cu₂S), malachite (CuCO₃*Cu(OH)₂) and chalcopyrite (CuFeS₂). Copper is naturally found in all plants and animals and is an essential element (in low concentrations) for all living beings (ATSDR, 2004).

Copper is a much used metal, primarily due to its properties as a durable, flexible, malleable metal which can conduct electricity and heat. It is primarily used as a metal in alloys (such as bronze and brass). A minor amount of copper is also used as a constituent in the production of copper compounds, primarily copper sulphate (ATSDR, 2004).

The use of copper is distributed throughout the industry sector as follows: construction (39%), electrical products (28%), transport equipment (11%), industrial machinery and equipment (11%) and consumer products (11%). The 10 most important markets for copper and copper alloys in 1986 were piping, building cables, telecommunication, power stations, equipment for use in plants, air-condition, electrical and non-electrical equipment for the car industry, electronics for the industry and industrial valves and fittings (ATSDR, 2004).

Copper compounds are used in the agriculture as fungicides, algicides, insecticides and pesticides. Furthermore, copper sulphate is used in the industry during production of azo-dyes and textile dyes as well as during refining of petroleum (ATSDR, 2004).

Finally, during many thousands of years copper has been used for production of jewelleries. One of the reasons why copper is used in jewelleries is that copper is the only other metal except from gold which naturally gives a red or yellow colour in alloys. Other reasons are that it is very resistant to corrosion and easy to prepare for plates, threads and similar as well as it is reasonably easily accessible and relatively harmless to work with.

6.3.2 Identification

6.3.3 Physical and chemical properties

6.3.4 Oral absorption

Copper absorption has been examined in 11 young men who had copper administered through the food in different concentrations. The apparent absorption varied inversely by the intake via the food (ranking from 67% at 0.38 mg/day to 12% at 7.53 mg/day). However, a study by Turnland et al. (1998) showed a real absorption of up to 77% (WHO, 2004a). Real absorption shall be regarded as the part of the copper which is absorbed in the organs, i.e. the amount ingested deducted the amount excreted via faeces/urine. Turnland et al. carried out another study in 2005 regarding oral absorption of copper. This study is described in the Copper Industry’s draft for a risk assessment of copper in 2006 but did not show higher values than 77%.

However, several factors can influence the absorption of copper. These factors include the amount of copper in the food, content of other metals (such as zinc, iron and cadmium) and age (ATSDR, 2004). The amount of accumulated copper does not seem to influence the absorption of further copper amounts in humans. Also, there does not seem to be a difference between the absorption in men and women (ATSDR, 2004).

Based on the information above the oral absorption of copper in this project is assumed to be 77%.

6.3.5 Dermal absorption

According to the Copper Industry’s draft for a risk assessment of copper from 2006 (Cross et al., 2006) the available data show that the metal copper and copper compounds can be absorbed through the skin.

According to the risk assessment (Cross et al., 2006), two non-published studies by Roper (2003) and Cage (2003) give the best data regarding dermal absorption of copper in humans. Based on these studies the risk assessment states that a dermal absorption factor of 0.3% applies for insoluble copper compounds (i.e. including copper chloride). This value derives from the highest value measured for copper in receptor fluid added with a value for copper retained in the skin and rounded up to follow a conservative approach. Thus, in these figures they include copper absorbed in the skin as OEDC orders that this has to be included. According to the risk assessment there is no evidence for dermal absorption of copper being larger for soluble compounds than for insoluble compounds. Thus, they recommend using the value of 0.3% for both types of compounds.

Based on this information the dermal absorption of copper in this project is assumed to be 0.3%.

According to Baars et al. (2001) copper can penetrate the skin when it is added in association with salicylic acid or phenyl butazone. However, the rate and scope of the dermal absorption in these cases are not known and therefore the dermal absorption rate of 0.3% is maintained. However, salicylic acid is known to be an ingredient in many skin care products^[4] while phenyl butazone is primarily used for treatment of pains (in among others horses) ^[5].

6.3.6 Distribution

Copper is an essential element. According to WHO (1996) referred in Baars et al. (2001) a daily intake of 20 to 80 µg/kg bw is necessary.

Regarding oral intake of copper the absorption of copper will primarily take place from the stomach and the small intestine. However, different copper compounds will be absorbed from different places (ATSDR, 2004). Immediately after intake of copper an increase in the concentration of copper in the blood follows. Thereafter the copper is transported to (and ends in) liver and kidneys. From the liver the copper can be transported to other tissues (ATSDR, 2004).

The half-life of copper in the different organs is 3.9 and 21 days (liver), 5.4 and 35 days (kidneys) and 23 and 662 days (the heart) respectively. The first value represents ceruloplasmine bound to copper (ATSDR, 2004) while the identity of the other is not clearly stated in the reference.

Copper is primarily excreted via the bile. Normally between 0.5 and 3% of the daily intake of copper will be excreted through the urine (ATSDR, 2004).

6.3.7 Local irritation and allergy

Copper and copper salts can generate allergic reactions by contact with the skin in sensitive individuals. Symptoms includes itch, flush, swelling and vesiculation. Studies have identified a sensitivity reaction at exposure of 0.5 – 5% of copper sulphate in water or petroleum during 24-48 hours (WHO, 1998).

In a few individuals exposure to copper has shown to cause pruritus dermatitis which is itching without visible changes of the skin (ATSDR, 2004). A study has reported a case where a woman had pruritus on her ring finger and wrist as a result of the content of copper in her ring and wrist watch (Saltzer and Wilson, 1968 in ATSDR, 2004). Furthermore, allergic reactions have been observed in individuals after a test with a copper coin and/or a copper sulphate solution (Barranco, 1972; Saltzer and Wilson, 1968 in ATSDR, 2004).

6.3.8 Acute toxicity

Acute toxicity as a result of ingestion of copper is rare in humans. However, it can occur through consumption of water containing copper or by intentional/accidental intake of large amounts of copper salts.

The acute lethal dose for adults is between 4 and 400 mg copper(II) ions per kg bodyweight. These values are based on data from suicide attempts as well as unintended intake of high amounts of copper (WHO, 2004a). Symptoms as a result of intake of large amounts of copper include vomiting, apathy, acute haematological anaemia, kidney and liver injuries, neurotoxicity, increased blood pressure and breathing. In some cases, coma and death follow (ATSDR, 2004).

Studies have shown that 13 out of 53 humans died following an intake of copper in amounts ranging from 6 to 637 mg/kg (copper sulphate). Death, presumable as a result of among other things failure in the central nervous system and kidney injuries, has also been reported in humans who had consumed water containing > 100 mg of copper sulphate per litre (Akintonwa et al., 1989 in ATSDR, 2004).

6.3.9 Long-lasting, repeated effect and gene-damaging effects

Generally, the toxicological effect arises at a structural change/weakening of the sites to which metals bind themselves or when copper binds itself to macro-molecules and enzymes. Furthermore, copper can react with peroxide and create radicals, which can cause damages to the cells. Toxic damages can also be generated by metal-lothioneine becoming saturated with copper (Baars et al., 2001). Lack of copper leads to effects, which are just as critical as the toxic effects related to intake of too much copper.

Several studies have examined possible liver damages in new-borns as a result of copper exposure through drinking water. A NOAEL value of 0.315 mg Cu/kg/day was identified following a study regarding intake of copper sulphate from drinking water (during a period of 9 months) (Olivares et al., 1998 in ATSDR, 2004).

A LOAEL value of 4.2 mg Cu/kg bw/day has also been reported in relation to  reduced bodyweight in mice after chronic oral exposure of copper gluconate (ATSDR, 1990 in Baars et al. (2001)).

6.3.10 Tolerable daily intake - TDI

A TDI value of 10 µg/kg/day, suggested by ATSDR (2004), is significantly below the recommended daily dose for intake of copper (20-80 µg/kg/day) and therefore this value is not used.

Vermeire et al. (1991), however, suggest a TDI value for copper of 140 µg/kg bw/day. Data from a RIVM report^[6] confirms a tolerable daily intake of 140 µg/kg bw/day. To evaluate whether the value stated by Vermeire et al. (1991) still is valid, Baars et al. (2001) have reviewed literature published since 1991(including ATSDR, 1990; IPCS, 1998; WHO, 1996; WHO, 1998). Among other things, they found the above LOAEL value of 4.2 mg Cu/kg bw/day. Baars et al. (2001) converted this value into a TDI value of 4 µg/kg bw/day. Here they used a safety factor of 1000 (10 for going from LOAEL to NOAEL, 10 for extrapolating experimental results from animal studies to humans and 10 for accounting for variation between humans). However, this TDI value turned out to be far below the minimum requirement for daily intake of copper (20 – 80 µg/kg bw/day). Therefore, Baars et al. (2001) recommended to use the TDI value (140 µg/kg bw/day) suggested by Vermeire et al. (1991).

Based on the above information a TDI value for copper of 140 µg/kg bw/day is assumed for use in this project.

Adjustment of TDI values due to background exposure

As mentioned earlier, TDI values shall be regarded as the amount of  substance which a human can tolerate to take in on a daily basis during a life time without experiencing health related effects. Therefore, it is important to take into account the amount of copper which each individual already takes in via air, food and water.

Background exposure of copper via food and beverages in Denmark

According to a report from the Danish Environmental Protection Agency (2000) ^[7], the normal Danish intake of copper among adults (60 kg) is 2.9 mg/day, corresponding to 48.3 µg/kg/day. According to Fromberg et al. (2005) 2 year old children (15 kg) ingest 59% of the adults’ food consumption which recalculated corresponds to a background exposure of (0.59×2.9/15) 114.1 µg/kg/day. Here it is assumed that the value stated in the report from the Danish Environmental Protection Agency deals with an exposure from food as well as water.

Background exposure of copper via the air in Denmark

According to the report ”The Danish Air Quality Monitoring Programme” from 2006 (prepared by the National Environmental Research Institute) (Kemp et al., 2007) the highest measured average value for a content of copper in the air in Denmark is 50.5 ng/m³ (the value measured on “Jagtvej” in Copenhagen). In order to choose a conservative approach this value is used to estimate which amount of copper an adult in Denmark inhales via the air.

According to the TDG an adult inhales 18 m³ air a day, while a 5 year old child (20 kg) inhales 11 m³ a day. I.e. an adult (60 kg) inhales (18m³×50.5ng/m³/1000) 0.909 µg copper per day. Converted into per kilo bodyweight (60 kg) this corresponds to 0.015 µg/kg bw/day. For children (20 kg) applies that they inhale (11 m³×50.5 ng/m³/1000) 0.556 µg copper per day which corresponds to 0.028 µg/kg bw/day.

Total background exposure

Because the TDI value as mentioned previously represents the amount of substance that a human as maximum can take in per day (during a life time) without causing health related effects, the TDI value is subtracted the above mentioned data for background exposure. Thereby a number is reached (”Margin to TDI value”) representing the ”extra amount” of copper that a human can take in on a daily basis (besides what a human is exposed to through food, beverages and air) without experiencing health damaging effects. This value is compared in the risk assessment with the amount that humans are exposed to by wearing or sucking the jewellery examined in this project.

Table 6-4: Background exposure of copper in Denmark as well as “Margin to TDI value” (µg/kg bw/day).

NB: * The value related to air is an average value from the monitoring station in Denmark which has shown the highest average. ** The value for copper consumption from food and beverages in children is based on the intake by 2 year old children (15 kg).

If people live in areas where they are exposed to a higher background concentration than the one mentioned above, the health risk by using the examined jewelleries in this project will be underestimated.

6.4 Nickel

6.4.1 Occurrence and use

Nickel occurs in nature primarily as oxide or sulphide compounds. The earths crust consists of 6% nickel, but nickel is also found in meteorites and on the sea bed as minerals (ATSDR, 2005a).

Pure nickel is a hard, silver-white metal, which is easy to mould. Furthermore it is ferromagnetic and a good conductor of heat and electricity. Nickel is often used in alloys with iron, copper, chromium or zinc. Here it is often used to help increase among other things the hardness and strength of the metal (ATSDR, 2005a).

The different alloys are used in different situations. Copper/nickel alloys are for instance used in coins, pipe laying, maritime equipments, petrochemical equipment, heat exchangers, pumps and electrodes for welding, while nickel/chromium alloys typically are used for heating elements. Furthermore, large amounts of nickel/iron alloys are used for producing steel alloys, corrosion-resistant steel and cast iron (ATSDR, 2005a).

Other nickel compounds include chlorine, sulphur and oxygen. Many of these nickel compounds are soluble in water and are used for among other things nickel coating, colouring of ceramics and for batteries (ATSDR, 2005a).

Finally, nickel is used in jewelleries. In this context nickel is frequently used as “sub-coating” for golden surfaces, since this results in a more shining gold coating. Nickel also forms diffusions barriers which prevent the metal from the parent material to diffuse to the surface, and thereby deteriorates the look of the jewellery.

6.4.2 Identification

6.4.3 Physical and chemical properties

6.4.4 Oral absorption

The Danish Environmental and Protection Agency has in 2006 performed a risk assessment of nickel and nickel compounds (Andersen et al., 2006), in which they conclude that based on a number of studies, an oral absorption value of 30% should be used for risk assessments. This value refers to oral absorption of the following nickel compounds: nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate in fasting people. For non-fasting people a value of 5% is recommended.

A study has shown that the bioavailability of nickel is reduced when nickel is given along with full-cream milk, coffee, tea or orange juice (ATSDR, 2005a). Other studies have shown a maximum nickel uptake of between 11.07 and 37.42%. Here nickel (12 µg/kg) was administered 4 hours after ingestion of scrambled eggs. The lowest absorption values (2.83-5.27%) were measured in people who had nickel administered along with a meal (Nielsen et al., 1999 in ATSDR, 2005a) (it was not specified which kind of nickel compound that was used in the study). Another study indicates that nickel absorption reduces with age (Hindsen et al., 1994 in ATSDR, 2005a).

Animal studies have shown that different nickel compounds are absorbed differently. The following absorption values were measured in a study using rats. Nickel oxide (0.01%), metallic nickel (0.09%), black nickel oxide (0.04%), nickel sulphide (0.47%), nickel sulphate (11.12%), nickel chloride (9.8%) and nickel nitrate (33.8%). Generally, the absorption was higher for soluble nickel compounds (ATSDR, 2005a).

In this project it is assumed that the oral absorption of nickel is 30%. The line of reasoning is that the source, which provides this value, is a comprehensive report from 2006, which has made a thorough review of a number of studies. Thus, it is assumed to represent the latest knowledge in the area. Furthermore, the value refers to nickel compounds which are relevant for this project (among these nickel chloride). The value is valid for fasting people, but in order to stick to a conservative approach the value is used anyway.

6.4.5 Dermal absorption

The risk assessment of nickel from 2005 (Andersen et al., 2005a – draft) concludes that absorption of nickel through the skin can occur but that a large proportion of the added dose remains on the skin. They state that limited data is available regarding exactly which fraction that is absorbed, but apply a value of 0.2% regarding dermal absorption of nickel for use in risk assessments. The value is based on an in vivo study in humans (Hostýnek et al. 2001 in Andersen et al., 2005a - draft).

Andersen et al. (2006), however, concludes that for use in risk assessments a value of 2% should be applied, related to dermal absorption of nickel following exposure of nickel chloride. Regarding exposure of nickel metal they recommend a value of 0.2% (based on a study of Hostýnek et al. 2001).

For use in this project a value of 2% is applied in terms of dermal absorption of nickel chloride, since this metal compound exists in sweat that is in contact with jewellery.

6.4.6 Distribution

Nickel is bound to serum proteins in the blood and is transported around the body. Nickel is subsequently concentrated in kidneys, liver and lungs as well as the lymph nodes (Baars et al., 2001).

A study examining individuals who were not on a daily basis exposed to nickel through work showed that the highest concentration of nickel was found in the lungs, followed by the thyroid gland, the suprarenal glands, the kidneys, the heart, the liver, the brain, the spleen and the pancreas (ATSDR, 2005a). A study has furthermore showed that nickel can cross the placenta, which was confirmed by increasing concentrations of nickel in mice foetuses whose mothers have been exposed to nickel during the pregnancy (ATSDR, 2005a).

6.4.7 Local irritation and allergy

Nickel can cause skin allergy and fulfils the criteria for being classified with the following risk phrase: R43: May cause sensitization by skin contact. According to Andersen et al. (2006) it is the Ni²⁺ ion, which is responsible for the immunological effects of nickel.

Available data shows that as long as a migration rate of 0.5 µg Ni/cm²/uge is not exceeded, there is no risk of causing skin allergy in non-sensitive individuals in a large part of the population (who are exposed to nickel and nickel alloys for an extended period of time) (Andersen et al., 2005a – draft).

According to the risk assessment of nickel from 2005 (Andersen et al., 2005a – draft) there is no simple correlation between the content of nickel and the release of nickel (related to a study of coins). Likewise they mention that when one is to evaluate the risk of sensitization due to nickel, it is the concentration of nickel ions per cm² skin that is interesting and not the total dose of nickel on the skin.

Contact dermatitis caused by nickel allergy is a well-known phenomenon. Contact dermatitis was found in 15.5% of 75,000 individuals who participated in a test with nickel sulphate (Uter et al., 2003 in ATSDR, 2005a), which demonstrates that it is a common reaction (ATSDR, 2005a). The majority of the cases of nickel allergy is caused by skin contact with metallic products such as earrings, jewelleries and buttons (European Environmental Contact Dermatitis Group, 1990 in Andersen et al., 2006).

A study of school children in the age of 7-12 years showed that among children with pierced ears 30.8% had nickel allergy while among the children who did not have pierced ears only 16.3% were allergic to nickel (Dotterud and Falk, 1994 in ATSDR, 2005a).

The majority of nickel tests are made using nickel sulphate since this substance is less irritating than nickel chloride. However, nickel alloys which are in contact with sweat form nickel chloride. Thus it is more relevant to perform nickel studies using nickel chloride (Menné, 1994 in ATSDR, 2005a). Menne and Calvin (1993) quoted from ATSDR (2005a) examined skin reactions related to different nickel chloride concentrations in 51 sensitive and 16 non-sensitive people. At a concentration of 0.01% no reaction was observed. At a concentration of 0.1% reactions in 4 out of the 51 people were observed.

All in all it is concluded in the EU risk assessment of nickel and nickel compounds from 2006 (Andersen et al., 2006) that there is not enough data available regarding dermal exposure of nickel chloride to determine which dose that triggers a reaction.

6.4.8 Acute toxicity

There is no indication of nickel being an essential element (as for instance copper). Thus the body does not require nickel.

Regarding acute nickel poisoning nickel carbonyl, a fugitive fluid of Ni(CO)₄, is the most critical. The effects of acute nickel carbonyl poisoning include headache, dizziness, nausea, vomiting, sleeplessness and irritation followed by symptoms which resemble pneumonia (WHO, 1991).

A study (Daldrup et al., 1983 in ATSDR, 2005a) has reported a death of a 2 year old child following ingestion of 570 mg Ni/kg (crude estimate) in the form of nickel sulphate crystals. Four hours after ingestion heart failure occurred and the child died 8 hours after ingestion.

Studies have indicated that soluble nickel compounds are more toxic than less-soluble nickel compounds. Oral LD₅₀values related to nickel sulphate of respectively 46 mg Ni/kg (female rats) and 39 mg Ni/kg (male rats) have been reported (Mastromatteo, 1986 in ATSDR, 2005a). Likewise, oral LD₅₀ values related to nickel acetate of 116 (female rats) and 136 mg Ni/kg (male rats) respectively have been reported (Haro et al., 1968 in ATSDR, 2005a).

Oral LD₅₀values for less-soluble nickel oxides and –subsulphides have been reported to >3.930 and > 3.665 mg Ni/kg respectively (Mastromatteo, 1986 in ATSDR, 2005a).

According to ATSDR (2005a) the lowest value reported (related to oral ingestion) is 39 mg/kg/day. This value is derived from a study in which a male rat ingested nickel sulphate (Mastromatteo, 1986 in ATSDR, 2005a). The lowest value reported in terms of systemic effects caused by acute exposure is a NOEAL value of 0.014 mg/kg/day. This value is reported in relation to dermatitis in nickel-sensitive humans. Nickel was administered in the form of nickel sulphate (ATSDR, 2005a).

6.4.9 Long-lasting, repeated effect and gene-damaging effects

Chronic effects caused by nickel exposure include among other things sinusitis and asthma. Extremely high risk of lung cancer has furthermore been reported amongst workers in nickel refineries. The workers were exposed to nickel subsulphides, nickel oxides and possible nickel sulphate (WHO, 1991).

The lowest NOAEL value reported related to medium long and long exposure of nickel to humans is according to ATSDR (2005a) 20 µg/kg/day. This value is reported in relation to a study in which 8 nickel sensitive humans gradually ingested increasing doses of nickel sulphate (in tap water) over a period of 91-178 days. At the reported value no individuals showed signs of health related effects on the skin (Santucci et al., 1994 in ATSDR, 2005a).

The lowest NOAEL value related to chronic exposure is according to IRIS (1996) related to a study by Ambrose et al. (1976). In this study a NOAEL value of 5000 µg/kg/day related to reduction in bodyweight in rats was reported (the study was completed over a period of 2 years). Nickel was administered as nickel sulphate

Nickel compounds are according to IARC (1997) carcinogenic in humans, while metallic nickel is potential carcinogenic in humans.

Baars et al. (2001) was not able to find new relevant data (after 1990) regarding toxicity caused by oral exposure of nickel or nickel compounds in humans or animals. Thus, they concluded that the TDI value of 50 µg/kg bw/day suggested by Vermerie et al. (1991) (and CEPA (1993), WHO (1996) and ATSDR (1997) in Baars et al., 2001) still is valid.

The study from which the TDI value of 50 µg/kg bw/day was derived is a study performed by Ambrose et al. in 1976. The study found, as described above, a NOAEL value of 5000 µg Ni/kg bw. The study included a 2-year study of rats and the effects observed were reduced bodyweight and higher heart/bodyweight ratio. A later study by American Biogenics Corp. (1988) likewise found a NOAEL value of 5000 µg/kg/day.

The EU risk assessment of nickel sulphate from 2005 (Andersen et al., 2005b – draft) arrives at two NOAEL values for use in risk assessment. One is a NOAEL value of 2200 µg/kg bw/day for oral administration of nickel – derived from a chronic cancer study. The effects at high exposure level were reduced survival in female rats and reduced bodyweight in both sexes. The other NOAEL value is based on a two-generation study of rats (exposed to nickel sulphate) and is related to effects (increased perinatal mortality in the offspring) during the development process. The NOAEL value for the dam was 1100 µg Ni/kg bw/day. Regarding the offspring (dosed after the perinatal period), a NOAEL value of 2200 µg Ni/kg bw/day was identified (Larsen and Tyle, 2008 - draft), since no effect was found in the offspring.

WHO (2007) uses a TDI value of 11 µg/kg/day. This value is calculated based on a NOAEL value of 1100 µg/kg bw/day and by use of a safety factor of 100 (10 for variation between species and 10 for variation within species).

Based on the above mentioned information a NOAEL value of 1100 µg/kg bw/day is assumed to be valid for use in this project.

6.4.10 Tolerable daily intake - TDI

Nickel allergy is already regulated since the release of nickel from products which are meant to be in long-lasting contact with the skin (such as jewellery) must not exceed 0.5 µg /cm² /week^[8]. Likewise piercing jewellery must not release more than 0.2 µg/cm² /week^[9]. This value is set at such a low level that skin allergy caused by dermal nickel exposure should not occur.

The risk assessment of nickel sulphate from 2005 (Andersen et al., 2005b) gives a NOAEL value of 1100 µg/kg/day related to damaging effects on the foetus. This NOAEL value is converted to a TDI value of 4.4 µg/kg/day by using a safety factor of 250 since the risk assessment states the use of a total safety factor of 200-300. The total safety factor is derived from the combination of a factor of 10 used for extrapolating the results from animal studies to humans; a factor of 10 for variation between humans and finally a factor of 2-3 in order to take into consideration the severity of the effects in question (death of foetuses).

For use in this project a TDI value related to nickel exposure (in women) of 4.4 µg/kg/day is used.

Regarding children a supplement to the EU risk assessment from 2008 has judged that the best basis for establishing a tolerable dose for children is a NOAEL value of 2200 µg/kg/day based on a two-generation study- and dosage of the offspring. By using a safety factor of 100 a TDI value of 22 µg/kg/day for children is achieved (Larsen and Tyle, 2008 – draft). The value related to children is thus higher which means that they are less sensitive than pregnant women.

Adjustment of TDI due to background exposure

As for the other metals humans are also exposed to nickel via other sources such as food, water and air. Thus, it is necessary to take into consideration the background exposure in order to identify the amount of nickel which humans in Denmark can tolerate to get “additionally” per day, without causing health related effects.

Background exposure of nickel via food and beverages in Denmark

According to a report from the Danish Veterinary and Food Administration (Fromberg et al., 2005) the background exposure of nickel from food in Denmark is in average 109 µg/day which corresponds to (109/60) 1.817 µg/kg bw/day. Fromberg et al. (2005) does not state a number related to children (4-6 years) regarding nickel exposure from food. However, Fromberg et al. (2005) states that 2 year old children (15 kg) take in 59% of the amount of food which adults consume. Based on these numbers an average background exposure of nickel via food and beverages in children of ((0.59x109)/15) 4.288 µg/kg bw/day is achieved.

Fromberg et al. (2005) also states a background exposure in terms of 95 percentiles (i.e. a value representing the maximum amount that 95% of the population is exposed to). If these values are used a background exposure for adults of (197/60) 3.283 µg/kg bw/day is achieved. For children the value is ((0.59x197)/15) 7.749 µg/kg bw/day.

Background exposure of nickel via air in Denmark

According to the report “The Danish Air Quality Monitoring Programme” from 2006 (prepared by the National Environmental Research Institute) (Kemp et al., 2007) the highest measured average value for content of nickel in air in Denmark was 5 ng/m³ (value measured in Aarhus, on the street “Banegårdsgade”). In order to choose a conservative approach this value is used to estimate the amount of nickel that an adult in Denmark inhales.

According to the TGD an adult inhales 18 m³ air per day, while a 5-year-old-child (20 kg) inhales 11 m³ per day. Thus, an adult (60 kg) inhales (18m³x5ng/m³/1000) 0.09 µg nickel per day which corresponds to 0.002 µg/kg bw/day. Children (20 kg) inhale (11 m³x5ng/m³/1000) 0.055 µg nickel per day which corresponds to an intake of cadmium via the air of 0.003 µg/kg bw/day.

Total background exposure

As the TDI value, as mentioned earlier, represents the maximum amount of substance that a person can tolerate to take in per day (throughout his/her entire lifetime) without experiencing health related effects, the TDI value is subtracted the above mentioned figures representing background exposure. Hereby a number is attained which represents the “extra addition” of nickel that humans can have on a daily basis (beside what they are exposed to via food, beverages and air) without causing health related effects. In the exposure scenarios this value is then compared with the amount of nickel that humans are exposed to by wearing or sucking the jewellery examined in this project.

Table 6-5: Background exposure of nickel and the “Margin to TDI value” (µg/kg bw/day).

NB: The 95 percentile relates to the numbers regarding background exposure via food and beverages (including tap water). * The value related to air is an average value from the monitoring station in Denmark which has shown the highest average in 2006. ** The value representing background exposure via food (for children) is based on 2 year olds (15 kg).

If people live in areas where they are exposed to a higher background concentration than the above mentioned, the health risk by using the examined jewelleries in this project would be underestimated.

Footnotes

^[1] Source: (http://www.ldaint.org/-information.htm#Info)

^[2] http://www.enhis.org/object_document/o4736n27387.html

^[3] http://www.netdoktor.dk/sunderaad/fakta/pigevaekstTabel.htm

^[4] http://da.wikipedia.org/wiki/Organisk_syre

^[5] http://en.wikipedia.org/wiki/Phenylbutazone

^[6] Information from IOM (2001) also confirms that the tolerable daily intake of copper is 10 mg per day.

^[7] http://glwww.mst.dk/udgiv/publikationer/2000/87-7944-304-4/html/kap13.htm

^[8] Statutory order on ban on import and sale of certain nickel-containing products. Stat. Ord. No. 24 of 14.01.2001.

^[9] Statutory order on change of statutory order on ban on import and sale of certain nickel-containing products. Stat. Ord. No. 789 of 12.08.2005.

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Version 1.0 October 2008, © Danish Environmental Protection Agency