Burden of Occupational and Environmental Hazards of Cancer

Abstract

Ecological studies showed the association of exposure to carcinogens present surroundings an indoor and outdoor environment. The International Agency for Research on Cancer (IARC) has classified arsenic, asbestos, benzene, radon gas etc. into group 1 carcinogens. In many countries, pollution is rising due to trend of increasing industrialization and urbanization, occupational exposure to asbestos and chemical carcinogens. Mostly in developing countries, women are traditionally leader in cooking but due to frequent use of biomasses and wood fuel in poor ventilated houses, they are exposed to indoor air pollutants. However, not only in developing countries, but also in developed countries like United States facing serious smoking problem where after smoking, radon is the second common cause of bronchogenic cancer. Smoking and radon exposure has synergistic effect on carcinogenesis. Adequate legislation like banning, elimination or substitutions of carcinogens in industries along with the public education can help in reduction of burden of the environmental and occupational cancer. This chapter is in process to explore the exiting occupational and environmental hazards present in the environment and causing several health diseases.

1 Introduction

Environment is everything outside the body that interacts with humans or living matter. Environment is derived from the French word “Environ” which means, “surrounding”. For human health and well-being, a clean environment is necessary. Interactions between environment and human health involves various pathways. Some substances found in environment can potentially lead to cancer, which has been defined as an uncontrolled division of cells. There are other complex factors in addition to carcinogens in the environment, which may lead to the development of cancer, including lifestyle and genetic makeup. Cancer is the second leading cause of death globally. Globocan report showed that cancer is responsible for an estimated 9.6 million deaths in 2018 (Bray et al. 2018). WHO reported that 19% of all cancer cases are attributable to the environment, including the workplace (IEPH 2016). The burden of environment related cancer deaths is 1.7 million deaths annually (Bray et al. 2018).

International Agency for Research on Cancer (IARC) classifies various compounds or physical factors, which can cause cancer (Cogliano et al. 2011).

• Group 1: “Carcinogenic to humans”—There is enough evidence to conclude that it can cause cancer in humans. Examples includes asbestos, benzene and ionizing radiation.

• Group 2A: “Probably carcinogenic to humans”—There is strong evidence of causing cancer in humans, but at present, it is not conclusive. Examples includes diesel engine exhaust, formaldehyde and PCBs.

• Group 2B: “Possibly carcinogenic to humans”—There is some evidence causing cancer in humans but at present, it is far from conclusive. Examples includes styrene and gasoline exhaust.

• Group 3: “Unclassifiable as to carcinogenicity in humans”—There is no evidence at present causing cancer in humans. Examples include anthracene, caffeine and fluorescent lighting.

• Group 4: “Probably not carcinogenic to humans”—There is strong evidence that not causing cancer in humans. Example is Caprolactam.

In the process of cancer formation, there is an activation of proto-oncogenes and the inactivation of tumor suppressor genes. Studies showed that combined effect of genetic and external factors acting concurrently and sequentially results in cancer formation (Lodish et al. 2000).

2 Cancer Risk from Environmental Exposure to Arsenic

Arsenic, a naturally occurring metalloid, is present in rock, soil, air, water and is constituted in animals and plant kingdom. The source of consumption of arsenic inside our body enters through the breathing air, drinking water, and the consumption of food. Inorganic compounds of arsenic found in industry, building products and arsenic-contaminated water has been linked to cancer (Arsenic cycle is shown in Fig. 1). Main source of environmental exposures to arsenic in some regions of the world is drinking water. An increased levels of arsenic occurs naturally in drinking water in various parts of Taiwan, Bangladesh, Japan and Western South America. Ground source of water like wells are rich source of arsenic as compared to water from lakes or reservoirs (Surface water). Based on the evidences from human studies, expert agencies like the “International Agency for Research on Cancer” (IARC) classifies arsenic as well as inorganic arsenic compounds as “carcinogenic to humans”. Arsenic exposure can result in carcinoma of the lung, urinary bladder and skin. Chronic exposure to this element usually results in carcinogenesis with a latency period of 30–50 years (Cogliano et al. 2011; Ratnaike 2003). Data published by Oberoi et al. (2014), showed that in every single year 9129–119,176 additional cases of urinary bladder cancer, 11,844–121,442 cases of bronchogenic cancer, and 10,729–110,015 cases of skin cancer globally are attributable to inorganic consumption of arsenic in food products.

Fig. 1

The arsenic cycle in nature

The maximum contamination level of arsenic allowed in drinking water in United Kingdom and United States of America is 10 μg/L (Andrew et al. 2017). The WHO confirmed a guideline level of 10 μg/L for inorganic arsenic in drinking water. Elevated arsenic concentrations in groundwater is found in certain locations like in Bangladesh. Countries like Bangladesh have adopted a guideline of 50 μg/L due to non availability of alternative water (Smith and Steinmaus 2009). In rural areas of Bangladesh, people depends on untreated groundwater for their drinking water consumption. Arsenic contaminated water when used for irrigation in agricultural settings also has an impact on crop yields. Rice is the primary source of calories in this country. A survey was done for estimation of arsenic levels in paddy soils of Bangladesh and results showed that in those zones where groundwater used for irrigation has high arsenic concentrations, and also where these tube wells were functional for the prolonged period of time, arsenic levels were elevated in these zones (Meharg and Rahman 2003). Study of nine hundred and one Polished White Rice Grain samples sourced from ten countries and four continents estimated cancer risks by multiplying daily arsenic intakes by the slope of internal cancer risk proposed by the Environmental Protection Agency. For a fixed consumption of “100” g intake of rice daily, median excess internal cancer risks were 7 in 10,000 for India, 15 in 10,000 for China, and 22 in 10,000 for Bangladesh (Mukherjee et al. 2006). In parts of Eastern India, arsenicosis due to environmental exposure is a serious public health concern. A case of double malignancy of bronchogenic as well as skin squamous cell carcinoma in 49 years old male has been reported by Sinha et al. (2016). Source of drinking water for this patient was from tube well which contains an increased level of arsenic (0.125 mg/L), where arsenic test was found positive in his hair and nail samples. He received chemotherapy (gemcitabine/carboplatin), followed by radiotherapy. There was complete response seen on radiological images. This case is a warning sign for public health concern for arsenic exposure in this part of India.

Prevention and Control: Provision of safe water supply for drinking, cooking and irrigation of crops can help the affected communities. Water with low arsenic can be utilized for food preparation, drinking and cultivation, and for bathing and washing clothes, high arsenic water can be used. Low-arsenic water with higher-arsenic water can be blended together for an acceptable arsenic concentration level. Rain water storage can be safe. Painting of tube wells or hand pumps with different colours symbolizing high or low arsenic concentration can help the people. Various techniques like oxidation, coagulation-precipitation, absorption and ion exchange are used for arsenic removal systems. The highly recommendable preventive and control methods can be considered by providing awareness through education to the communities living around affected areas (Flanagan et al. 2012; Diaz and Arcos 2015).

3 Asbestos (IARC Group 1 Carcinogen)

Asbestos is bundles of six naturally occurring longer thinner fibres of the mineral silicate of “serpentine” and “amphibole” series. These are serpentine mineral chrysotile (White asbestos) and 5 amphibole minerals which are actinolite, amosite (Brown asbestos), anthophyllite, crocidolite (Blue asbestos) and tremolite. All the commercial form of Asbestos are declared as human carcinogens by IARC. Asbestos market is captured and maintained by the urban industries involved in mining, manufacturing and handling of asbestos containing products. Epidemiological studies showed that high incidence of lung cancer, pleural, peritoneal mesotheliomas and gastrointestinal tract cancers were reported in the group of occupationally exposed to asbestos fibers (Kim et al. 2013). Government regulations have imposed permissible limits of 2 fibers/cm³ asbestos. Italy was the leader of asbestos production and consumer in Europe of 20th century until it was banned in 1992. Occupational exposure to asbestos occurs in mining and marketing of asbestos, shipyards, cement production, asbestos textured ceiling (Fig. 2) and textile industries (Marsili et al. 2017). India is one of eight countries that accounted for 80% of the world’s asbestos consumption including Russia, China, Kazakhstan, Ukraine, Thailand, Brazil, and Iran. According to US geological survey report, it was found that asbestos consumption increased in Asian countries like India, China, Kazakhstan and Ukraine.

Fig. 2

a Asbestos texured ceiling. b Pleural plaques due to asbestos exposure

Various studies showed the supra-additive effects of increase in lung cancer risk with asbestos, smoking and asbestosis. Lung cancer mortality among non-smokers increases with exposure to asbestos as shown by Markowitz et al. (2013). Public health challenge arises due to the decrease in asbestos usage by more developed countries and the burden is taken by less-developed countries that are continuing to use asbestos.

Prevention: Workers ‘Medical Screening Examination’ is must to identify early detection of risk factors and lung changes where intervention can have maximum benefit. Preplacement and periodic examination including blood, urine, exhaled air, pulmonary function tests, radiological examination of lungs to be done. An occupational exposure history and a respiratory health questionnaire must be recorded. Use of respiratory masks and protective clothing during occupational exposure can help the occupational workers. Employers must operate a medical surveillance program for all workers (Szeinu et al. 2000). Workers should be advised to quit smoking as already mentioned that smoking with simultaneous asbestos exposure has synergistic effect on likelihood of lung cancer regardless of the use of respiratory protection equipment (Hashim and Boffetta 2014). Three Es: Enforcement, Engineering and Education in the workplace can reduce the hazards.

4 Benzene Exposure

Report of “International Agency for Research on Cancer (IARC)” showed that the benzene is carcinogen substance in both animal and humans studies (McMichael 1988). Benzene is a light yellow liquid, flammable substance having aromatic odour. Route of entry into the body is through inhalation, ingestion and skin exposure. Metabolites of benzene from the liver like Benzoquinone and Mucoaldehyde causes toxicity in bone marrow. Benzene is used in organic solvent, inks in the printing industry, lubricants, dyes, cleaners, production of rubber, and pesticides in the chemical and pharmaceutical industries (Fig. 3). The benzene affect Hematopoietic Stem Cells (HSC) and differentiation steps of progenitor cells thus cause different type of haematological cancers derived from stem cell of hematopoietic system (Kauts et al. 2016). Benzene exposure occurs by breathing in air containing benzene, breathing second-hand smoke, burning coal and oil emissions, motor vehicle exhaust, and gasoline service stations evaporation. Data showed that about 50% of the exposure to benzene in the US results from tobacco smoking or from exposure to tobacco smoke. Benzene from gasoline can be permeated into the skin (Korte et al. 2000).

Fig. 3

Household and commercial chemical carcinogens those accumulated indoor and outdoor environment

Prevention: Reduction of benzene exposures like vehicle exhausts emissions can be minimized by reviewing and improving the designs and continuous monitoring of engine settings. Location and design of petrol filling stations policies should be strong. Domestic use of benzene-containing products should be avoided and infants and children to be isolated from vehicle emissions in indoor settings (Nazaroff 2013). Replacement or utilization of alternative solvents in industrial processes can help in risk reduction. One example of occupational aplastic anaemia reduction occurs in a Chinese shoemaking factory in China. Here four cases of aplastic Anaemia were detected among 211 workers over an eight-month period. No further case occurs once benzene was replaced by new solvent (Issaragrisil et al. 2006). Public awareness and educational activities required in industry and domestic sites.

5 Outdoor Air Pollution (OAP) in Urban Settings

Air pollution causes cancer confirmed by WHO. Reports of IARC concluded that outdoor air pollution causes cancer of lung and an increased risk for bladder cancer is linked with exposure to outdoor air pollution. Industrial sources, power plants, motor vehicles etc. release carcinogens into outdoor air (Fig. 4). In densely populated industrial urban territories, outdoor air contains human carcinogens like benzene, benzopyrene, and benzene soluble organics. The excess lung cancer risk associated with ambient air pollution is small as compared to cigarette smoking (Srogi 2007). More polluted cities like in China, OAP may contribute to as much as 10% of bronchogenic carcinoma overall, and may be a larger proportion is contributed in women who never smokes. As there is a lack of studies with robust data in developing world, most of conclusions are based on extrapolating the relative risk estimates from the ACS study to China, India, and other settings. Developing world has differences and variations in health status and composition of air pollution as compared to developed world, which results into uncertainties (Madaniyazi et al. 2015).

Fig. 4

Carcinogens, like diesel engine exhaust, solvents, metals, and dust are the main source of outdoor air pollution

6 Indoor Air Pollution

Indoor living habits, such as passive smoking, cooking on solid fuel like coal, biomass, wood, crop residues and inadequate ventilation systems produce numerous indoor air pollutants (Fig. 5). Tobacco smoke contains over 4000 chemicals in the form of particles and gases. Of the 4000 chemicals, 60 are carcinogens, including benzene, cadmium, formaldehyde and toluene. Smoking around the children results in second hand smoke (SHS). Children’s are higher risk by this SHS due to respiratory rate, which is slightly more than the adult counterparts and large lung surface area. An increased amount of nicotine from second hand smoke is found deposited on household surfaces, furniture, air and dust in the homes (Burton 2011).

Fig. 5

Indoor air pollution by incomplete combustion of wooden/bio fuel inside ill ventilated houses

An hour a day in a room with a smoker is nearly a hundred times more likely to cause lung cancer in a non-smoker than 20 years spent in a building containing asbestos-Sir Richard Doll.

Globally approx. 2.8 billion people depends upon solid fuels like coal, biomass and simple stoves. In developing countries, biomass fuels in open fires from wood and cake of animal dung and traditional stoves are used for extensive periods inside poorly ventilated dwellings. Thus leading to increased levels of household air pollution (HAP) exposure. Health damaging pollutants like carbon monoxide, sulfur oxides, nitrogen oxides, aldehydes, benzene, and particulate matters and polyaromatic compounds are emitted by smoke of coal and biomasses. Indoor coal combustion emissions are human carcinogens and defined in IARC Group 1. Concentrations of polycyclic aromatic hydrocarbons and other carcinogenic compounds in the wood smoke labelled as mutagenic. Evidence of genotoxic effects are seen in subjects exposed to wood smoke (Bruce et al. 2010).

Prevention: Educational public awareness is best method of prevention. Moreover, IAP associated with solid fuel use due to poor socioeconomic conditions can be alleviated by poverty reduction. IAP is a major concern for health of women and young children, who may spend many hours close to the fire. Stoves with flues that vent smoke to the exterior, cleaner fuels (LPG or kerosene) etc. should be provided by Government to poor communities with utilization of NGO services. The Indian National Programme of improved cook stoves was established in 1983 with targets like conserving fuel, reducing smoke emissions in the cooking area, improving health conditions and improving employment opportunities for the people living in rural areas with poor socioeconomic circumstances (Jeuland and Pattanayak 2012). Along with distribution of stoves, education is required regarding operating and maintaining of these durable stoves.

7 Radon Gas

Radon is chemically inert radioactive gas that is colourless and odourless. When atoms of uranium 238 decay, due to radioactive disintegration reactions they transformed into several series of other radioactive elements. The “fifth generation” is radium, and its decay generates radon. Uranium traces are easily found in earth’s rock and soil in most of the areas of United States. Depending on the underlying geology, its concentrations vary from place to place. The Environmental Protection Agency (EPA) report showed that radon is the 2nd leading cause of lung cancer in the United States which may killing 21,100 people per annum (Cao et al. 2017). The combined health effects of radon and tobacco exposure are synergistic rather than additive, so reducing either of the exposures substantially reduces lung cancer risks (Keith et al. 2012). Up to 20% of lung cancer mortality in the United States occur each year in an individuals, who have never smoked, and which may translates to about 30,000 Americans in 2017. Protracted exposure to radon is considered the most common cause of lung cancer in this population (Ou et al. 2018).

Half-life of radon gas is 3.8 days, as this is produced from rocks and soils, it has tendency to concentrate in enclosed spaces like underground mines or houses (Lugg and Probert 1997). Buildings design and construction and the quantity of radon in the underlying soil has impact on the magnitude of indoor radon concentration. Radon gas from the ground or soil into the houses can be entered due to vacuum created because of pressure differences between the house and the soil. Air pressure inside a home is often lower than the pressure in the soil especially near the basement floor slab and these air pressure differences allows the houses act as vacuum and there is the easy entry of radon gas inside the houses. Air Cracks in concrete floors and walls, construction joints, around pipe penetrations, or pores in hollow-block walls are route of entry of radon gas inside homes (Fig. 6). Radon gas released by well water during showering and other household activities is another source (Nielson et al. 1997).

Fig. 6

Uranium contaminated rocks, soil are the source of indoor radon gas exposure, which emit alpha particles, and these particles are inhaled and absorbed by lung tissue

7.1 How Radon Causes Cancer?

Radioactive decay of radon results in emission of Alpha particles, which are ionizing radiations. It also emits some radioactive short-lived decay products. Alpha particles can penetrate the sensitive and unshielded lung cells (Fig. 6) and thus causes damage to double helical strands of DNA. Picocurie (pCi) is rate of radioactive decay of radon. Four picocuries per liter of air (4 pCi/L) is the U.S. Environmental Protection Agency (EPA) recommended action level. The EPA recommends this level when owners of houses take action for radon reduction. EPA estimates that nearly one out of every fifteen homes in the United States has radon levels above the action level. One in three houses in Minnesota have been found radon levels above the action level (Levy et al. 2015a, b). Eight Universities and a few research Institutions in India participated in co-ordinated research project sponsored by the Board of Research in Nuclear Sciences (BRNS) of Department of Atomic Energy. The results show that the radon gas concentrations vary between 4.6 and 147.3 Bq/m³ in different regions with an overall geometric mean of 23.0 Bq/m³ (GSD 2.61). The geographical distribution pattern shows relatively high inhalation dose rates (>2.0 mSv/y) in the north-eastern part of India. Concentration of uranium and thorium in soil and rocks in northeast areas of India is quiet high. Results of this study showed that Indian dwellings in most areas do not require any action levels with respect to indoor radon due to good natural ventilation in Indian dwellings. Inhalation dose rates on higher side has been observed in the north-eastern part of the country is matter of concern (Pintilie et al. 2018). In another study, Radon (²²²Rn) in the drinking water of Dehradun City, which is a part of sub Himalayan ranges of India, from the tube wells and hand pumps was measured. Results showed that the values were observed to be more than the average of the recommendations. However, these values were below the highest recommended value of 400 Bq l⁻¹. As study concluded that the water used for drinking in this region is contaminated by radon but still there is lack of big data and more studies are required to explore the study area (Srinivasa et al. 2005).

7.2 Genotoxic Profiling of Radon Gas

Many previous studies are evident (Fig. 8) that radon are capable to inducing genotoxicity in human and other lab animals. Chromosomal aberrations, micronuclei, gene mutations (HPRT), sister chromatid exchanges and DNA damages like markers were noticed in the human peripheral and whole blood lymphocytes, Rat (tracheal epithelial cells), Rabbit (somatic cells), Mouse and rat bone marrow cells (Bilban and Jakopin 2005; Shanahan et al. 1996; Tuschl et al. 1980; Abo-Elmagd et al. 2008; Hornung and Meinhardt 1987).

7.3 Prevention from Radon Exposure (CGR 2012)

• 1. Testing radon at home is only way to find if people living in these houses are at risk or not. Environmental Protection Agency (EPA) and the surgeon general recommend fixing homes that have levels at or above 4 pCi/L (picocurie per liter). United States have radon programs and provide free radon test kits, which is not very expensive methods to fix and prevent high radon exposure in homes.

• 2. Sealing visible cracks is a basic part of most radon mitigation approached, but sealing alone is not enough.

• 3. For dilution of radon, opening of doors and windows may sometimes be effective, but it is not a practical long-term solution.

8 Ionizing Radiation and Cancer

Populations are exposed to radiation from environmental sources, such as nuclear reactor accidents and fallout from weapons testing. In addition, cancer risk occurs from background radiation and ultraviolet radiation. Ionizing radiations induce gene mutations and chromosome aberrations, which are known to be involved in the process of carcinogenesis (Thomas and Symonds 2016). Figure 7 shows different sources of radiation exposures.

Fig. 7

Various source of radiation increases mutational and cancer risks

Survivors of atomic bomb tragedy in Hiroshima and Nagasaki, who are followed for more than 50 years, provide the evidence based data on the carcinogenic effects of radiation in humans. Epidemiological studies showed that exposure to moderate to high doses of radiation increases the risk of cancer in most organs (Jordan 2016) (Fig. 8).

Fig. 8

Genotoxic impact of radon

The Life Span Study (LSS) cohort consists of about 120,000 survivors of the atomic bombings in Hiroshima and Nagasaki, Japan, in 1945. The Radiation Effects Research Foundation (RERF) and its predecessor, the Atomic Bomb Casualty Commission, have studied them. This is one of the longest study with large number of samples and follow up period 1950–2000. Leukaemia was the first cancer linked with radiation exposure in atomic bomb survivors (Folley et al. 1952) and has the highest relative risk of any cancer. Results provided by Pierce and colleagues showed that 78 of 176 (44%) leukaemia deaths among survivors with doses exceeding 0.005 Sv were due to radiation exposure (Little 2009).

Cancers of the breast, thyroid and lung risk estimates are fairly precise in addition to leukaemia’s, and associations have been found at relatively low doses (<0.2 Gy). Associations between radiation and cancers of the, colon, salivary glands, urinary bladder, ovary, central nervous system and skin have also been reported, but the relationships are not as well quantified. Persons exposed to irradiation for medical reasons have been studied. Medical radiation exposure results in non-uniform doses to the various organs of the body. Therapeutic procedures results in organ specific doses often as high as 40 or more Grey. Association of Leukaemia with medical radiation exposure is documented in many studies. Other medical radiation studies demonstrated a dose-response relationship for breast cancer (Shah et al. 2012). The latency period for radiation exposure cancers like induction of leukaemia is 5–7 years, and for solid tumours is at least 10 years. Radiation exposures by Ultraviolet rays is associated with 65% of melanoma cases and 90% of non-melanoma skin cancers including basal cell carcinoma and squamous cell carcinoma (Testa et al. 2017).

Epidemiological studies provided the “Dose-Response Relationships” for cancer induction following exposure to moderate to high doses of low LET radiation. Although some studies showed radiation effects below 100 mSv but still larger data and more studies are required to yield results which will be statistically significant (Suzuki and Yamashita 2012).

• Preventions

• (i) Unnecessary exposures as well as over-exposures can be prevented by principle of ALARA “As low as reasonably achievable”. Time, Distance, and Shielding are three primary means to keep body safe from radiation exposure (Edison et al. 2017).

  Time: Minimize the time of exposure to radiation will decrease the dose.

  Distance: The greater the distance between source of radiation and individual, the exposure will be decreased.

  Shielding: Shielding is useful for absorbing radiation energy and less of radiation dose is absorbed in the body’s tissues. Lead or Lead Equivalent Shielding for X-rays and gamma rays is an effective way to minimize the radiation exposure. When working in radiation areas lead glasses, lead aprons, mobile lead shields, and lead barriers can reduce the exposure to radiations.

• (ii) Labeling radioactive and potentially radioactive areas and items will help prevent the spread of contamination.

• (iii) Use of personal protective equipment (PPE) such as safety glasses, radiation protection gloves, laboratory coats, thyroid shields are good for prevention. The minimum protective lead equivalents in hand gloves and thyroid shields should be 0.5 mm (Hyun et al. 2016).

• (iv) Sign-ages in radiation areas like “no unauthorized entry” or “CONTROLLED RADIATION AREA” with colour recommended by authorities can make public aware of hazard areas.

• (v) Education and knowledge about safe handling of all levels of radiation is important to prevent or minimize possible biological effects (Awosan et al. 2016).

In summary, most of the occupational and environmental cancers are preventable. Strong policies should be originated from labour, environment, medical sector, health and other ministries involved in preventing occupational and environmental cancers. Moreover, research in the field of environmental carcinogens can be explored for more solutions.

9 Summary

• 1. Elimination of risk factors by primary prevention of cancer through mitigation of environmental and occupational determinants.

• 2. Policies and regulations for phasing out of replaceable processes or substitution of chemicals.

• 3. Promote safe measures for storage, disposal or recycling of chemicals.

• 4. Trade and transport of hazardous substances needs strong legislation (e.g. increasing taxes).

• 5. Public and alternative transportation systems to be utilized like promotion of pedestrian-oriented streets.

• 6. Standards for Radiation Protection like IAEA/BARC.

• 7. Education of practitioners to promote the use of referral guidelines.

• 8. Justification of radiological medical procedures.

• Control measures in the working environment

• 1. Identification and surveillance of exposure

• 2. Regulating the use of protective equipment for workers

• 3. Inclusion of occupational cancer in national lists of occupational diseases

• 4. Notification

• 5. Establishing national dose registries

• 6. Providing workers access to information, thus Empowering them

• Research in this area

• 1. Dose response for different types of cancers

• 2. Low-level exposures to carcinogenic pollutants

• 3. Environmental risks and genetic susceptibility.